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  • 1. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Karlsson, Susanne
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Uncoupling protein 2 mediates age-related mitochondria inefficiency and urinary protein excretionManuskript (preprint) (Annet vitenskapelig)
  • 2. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zheng, Xiao-Wei
    Grünler, Jacob
    Karlsson, Susanne
    Mazzone, Massimiliano
    Carmeliet, Peter
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Catrina, Sergiu-Bogdan
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hypoxia-inducible factors activation protects mitochondria function and prevents albuminuria in kidney-specific diabetic von Hippel-Lindau deficient miceManuskript (preprint) (Annet vitenskapelig)
  • 3. Carvalho, Carla
    et al.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zheng, Xiao-Wei
    Grünler, Jacob
    Karlsson, Susanne
    Mazzone, Massimiliano
    Carmeliet, Peter
    Inagi, Reiko
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Catrina, Sergiu-Bogdan
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Activation of hypoxia inducible factor due to reduced prolyl hydroxylase 2 activity prevents renal mitochondria dysfunction and improves cortical oxygenation in type 1 diabetic miceManuskript (preprint) (Annet vitenskapelig)
  • 4.
    Cat, Aurelie Nguyen Dinh
    et al.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Callera, Glaucia E.
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Sanchez, Ana
    Univ Complutense, Fac Farm, Dept Fisiol, Madrid, Spain..
    Dulak-Lis, Maria Gabriela
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Tsiropoulou, Sofia
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Montezano, Augusto C.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    He, Ying
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Briones, Ana M.
    Univ Autonoma Madrid, CIBER Enfermedades Cardiovasc, Sch Med, Dept Pharmacol, Madrid, Spain..
    Jaisser, Frederic
    Ctr Rech Cordeliers, INSERM Team 1 1138, Paris, France..
    Touyz, Rhian M.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.;Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 2952Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1 alpha. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.

  • 5. Franzen, Stephanie
    et al.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nangaku, Masaomi
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes2014Inngår i: American Journal of Physiology-Renal Physiology, ISSN 1931-857X, Vol. 306, nr 10, s. F1171-F1178Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.

  • 6.
    Friederich, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes2018Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 223, nr 4, artikkel-id e13058Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AimUncoupling protein-2 (UCP-2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP-2(-/-) mice, we tested the hypothesis that UCP-2-mediated leak respiration is important for the development of diabetes-induced intrarenal hypoxia and proteinuria. MethodsKidney function, invivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild-type and UCP-2(-/-) mice during normoglycaemia and 2weeks after diabetes induction. ResultsDiabetic wild-type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM-1 excretion. However, diabetic UCP-2(-/-) mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM-1 excretion. ConclusionAlthough functioning as an antioxidant system, mitochondria uncoupling is always in co-occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP-2-mediated mitochondrial leak respiration is necessary for the development of diabetes-induced intrarenal tissue hypoxia and proteinuria.

  • 7.
    Friederich Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.

         UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.

         The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.

         Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.

    Delarbeid
    1. Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
    Åpne denne publikasjonen i ny fane eller vindu >>Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
    Vise andre…
    2009 (engelsk)Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, s. 205-212Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.

    sted, utgiver, år, opplag, sider
    New York: Springer, 2009
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-102380 (URN)10.1007/978-0-387-85998-9_32 (DOI)000262627100032 ()19227473 (PubMedID)978-0-387-85997-2 (ISBN)
    Konferanse
    Annual Conference of the International-Society-on-Oxygen-Transport-to-Tissue
    Tilgjengelig fra: 2009-05-06 Laget: 2009-05-06 Sist oppdatert: 2017-12-13
    2. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
    Åpne denne publikasjonen i ny fane eller vindu >>Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
    Vise andre…
    2008 (engelsk)Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1777, nr 7-8, s. 935-940Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.

    Emneord
    Diabetes mellitus, kidney, mitochondria, uncoupling protein-2, oxygen consumption
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-110142 (URN)10.1016/j.bbabio.2008.03.030 (DOI)000257696400054 ()18439413 (PubMedID)
    Merknad
    Conference Information: 15th European Bioenergetic Conference Trinity Coll, Dublin, IRELAND, JUL 19-24, 2008 Tilgjengelig fra: 2009-11-04 Laget: 2009-11-04 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    3. Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes
    Åpne denne publikasjonen i ny fane eller vindu >>Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes
    Vise andre…
    2012 (engelsk)Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, nr 5, s. 1535-1543Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.

    Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

    Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 +/- 0.1 vs 0.2 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)), glomerular hyperfiltration (502 +/- 26 vs 385 +/- 3 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/24 h), mitochondrial fragmentation (fragmentation score 2.4 +/- 0.3 vs 0.7 +/- 0.1) and size (1.6 +/- 0.1 vs 1 +/- 0.0 mu m) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 +/- 9 vs 67 +/- 4 optical density; OD) but were reduced in CoQ10 treated groups (43 +/- 2 and 38 +/- 7 OD).

    Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

    Emneord
    db/db-mice, Kidney, Mitochondria, Type 2 diabetes, Uncoupling protein-2
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-167777 (URN)10.1007/s00125-012-2469-5 (DOI)000302994600036 ()
    Tilgjengelig fra: 2012-02-01 Laget: 2012-02-01 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    4. Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
    Åpne denne publikasjonen i ny fane eller vindu >>Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
    Vise andre…
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e39635-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-167782 (URN)10.1371/journal.pone.0039635 (DOI)000305966500017 ()
    Tilgjengelig fra: 2012-02-01 Laget: 2012-02-01 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    5. Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats
    Åpne denne publikasjonen i ny fane eller vindu >>Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats
    2013 (engelsk)Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, s. 217-223Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.

    sted, utgiver, år, opplag, sider
    Springer-Verlag New York, 2013
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-167783 (URN)10.1007/978-1-4614-4989-8_30 (DOI)000339280100031 ()978-1-4614-4771-9 (ISBN)978-1-4614-4989-8 (ISBN)
    Tilgjengelig fra: 2012-02-01 Laget: 2012-02-01 Sist oppdatert: 2018-01-12
    6. Increased mitochondria uncoupling results in kidney tissue hypoxia and proteinuria.
    Åpne denne publikasjonen i ny fane eller vindu >>Increased mitochondria uncoupling results in kidney tissue hypoxia and proteinuria.
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-167786 (URN)
    Tilgjengelig fra: 2012-02-01 Laget: 2012-02-01 Sist oppdatert: 2018-01-12
  • 8.
    Friederich Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Aslam, Shakil
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Nordquist, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e39635-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

  • 9.
    Friederich Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Franzén, Stephanie
    Catrina, Sergiu-Bogdan
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Dallner, Gustav
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Brismar, Kerstin
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes2012Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, nr 5, s. 1535-1543Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.

    Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

    Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 +/- 0.1 vs 0.2 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)), glomerular hyperfiltration (502 +/- 26 vs 385 +/- 3 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/24 h), mitochondrial fragmentation (fragmentation score 2.4 +/- 0.3 vs 0.7 +/- 0.1) and size (1.6 +/- 0.1 vs 1 +/- 0.0 mu m) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 +/- 9 vs 67 +/- 4 optical density; OD) but were reduced in CoQ10 treated groups (43 +/- 2 and 38 +/- 7 OD).

    Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

  • 10.
    Friederich-Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Nangaku, Masaomi
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Renal hypoxia due to increased oxygen metabolism is an independent pathway to nephropathy2014Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, nr 1, artikkel-id 890.6Artikkel i tidsskrift (Annet vitenskapelig)
  • 11.
    Friederich-Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Persson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Increased kidney metabolismas a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats2013Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 789, s. 9-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.

  • 12.
    Friederich-Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Thorn, Erik
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nangaku, Masaomi
    Levin, Max
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress2013Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, nr 5, s. 914-919Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

  • 13.
    Friederich-Persson, Malou
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Welch, William J.
    Luo, Zaiming
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells2014Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, s. 157-163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO(2)). We investigated the effect of Ang II on QO(2) in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO(2) was determined during baseline (113 mmol/l NaCl; transport-dependent QO(2)) and during sodium-free conditions (transport-independent QO(2)). Ang II reduced transport-dependent QO(2) in wild-types, but not in p22(phox) which also displayed increased QO(2) at baseline. Transport-independent QO(2) was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO(2) in wild-type. Addition of H2O2 reduced transport-dependent QO(2) in wild-types, but not in p22(phox). Transport-independent QO(2) was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO(2) suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO(2) was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO(2) was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO(2) in proximal tubular cells and may be an important pathway modulating renal QO(2).

  • 14.
    Lefranc, Clara
    et al.
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Braud, Laura
    Univ Paris Est Creteil, INSERM, Dept Pathophysiol Cardiovasc & Resp Dis, Dev & Senescence,U955,Team 12, Creteil, France.
    Palacios-Ramirez, Roberto
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Karlsson, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Boujardine, Nabiha
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Motterlini, Roberto
    Univ Paris Est Creteil, INSERM, Dept Pathophysiol Cardiovasc & Resp Dis, Dev & Senescence,U955,Team 12, Creteil, France.
    Jaisser, Frederic
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Cat, Aurelie Nguyen Dinh
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity2019Inngår i: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, nr 2, s. 458-468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.

  • 15.
    Lefranc, Clara
    et al.
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France.
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palacios-Ramirez, Roberto
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers,UMRS 1138, Paris, France.
    Cat, Aurelie Nguyen Dinh
    Paris Descartes Univ, Pierre & Marie Curie Univ, INSERM, Ctr Rech Cordeliers,UMRS 1138, Paris, France.
    Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor2018Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 238, nr 3, s. R143-R159Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called 'adipokines', including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin-angiotensin-aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.

  • 16. Lindahl, Emma
    et al.
    Nordquist, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Müller, Patrick
    El Agha, Eli
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Dahlman-Wright, Karin
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jörnvall, Hans
    Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells2011Inngår i: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, nr 7, s. 697-704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.

  • 17.
    Nordquist, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Liss, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Shoji, Kumi
    Nangaku, Masaomi
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy2015Inngår i: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, nr 2, s. 328-338Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

  • 18. Papazova, Diana A.
    et al.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Joles, Jaap A.
    Verhaar, Marianne C.
    Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension2015Inngår i: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 308, nr 1, s. F22-F28Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney QO(2), cortical PO2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 +/- 3.3 vs. 0.9 +/- 0.4 pmol O-2.s(-1) .mg protein(-1), P < 0.05) and increased whole kidney Q(O2) (55 +/- 16 vs. 33 +/- 10 mu mol O-2/min, P < 0.05). Corticomedullary P-O2 was lower in TX compared with 1K-CON (30 +/- 13 vs. 47 +/- 4 mu M, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Q(O2), P-O2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage.

  • 19. Papazova, Diana A.
    et al.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Koeners, Maarten P.
    Joles, Jaap A.
    Verhaar, Marianne C.
    Donor Pretreatment with Mitotempo Decreases Mitochondrial Uncoupling after Experimental Renal Transplantation2014Inngår i: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, s. 533-533Artikkel i tidsskrift (Annet vitenskapelig)
  • 20.
    Persson, Malou Friederich
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats2013Inngår i: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, s. 217-223Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.

  • 21.
    Persson, Patrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Inagi, Reiko
    University of Tokyo Graduate School of Medicine, Tokyo, Japan.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress2015Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, nr 3, s. 311-318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. The present study investigates if chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats.

    METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers.

    RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness.

    CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.

  • 22.
    Schiffer, Tomas A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mitochondrial Reactive Oxygen Species and Kidney Hypoxia in the Development of Diabetic Nephropathy2017Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, artikkel-id 211Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy.

  • 23.
    Sivertsson, Ebba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Uppsala Univ, Div Integrat Physiol, Dept Med Cell Biol, Uppsala, Sweden.
    Friederich Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Öberg, Carl M.
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Fasching, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Rippe, Bengt
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability2018Inngår i: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 314, nr 5, s. F864-F872Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

  • 24.
    Sivertsson, Ebba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Friederich-Persson, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Inhibition of Mammalian Target of Rapamycin Induces Renal Mitochondrial Uncoupling in Rats2013Inngår i: Oxygen Transport To Tissue XXXV, 2013, s. 309-314Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The mechanisms underlying diabetic nephropathy are not fully understood. However, recent research indicates mitochondria dysfunction as a contributing factor. Mammalian target of rapamycin (mTOR) is a known regulator of mitochondria function and could therefore also be involved in the development of diabetic nephropathy. The present study investigates the role of mTOR for controlling the function of mitochondria isolated from normal and diabetic rat kidneys. Control and streptozotocin-induced diabetic rats were treated with the mTOR inhibitor rapamycin (0.2 mg/day) by oral gavage for 14 days, after which mitochondria function was investigated using high-resolution respirometry. Mitochondrial uncoupling was defined as increased oxygen usage unrelated to ATP production. mTOR inhibition induced mitochondria uncoupling in control rats, but did not affect the already occurring uncoupling in kidney mitochondria from diabetic animals. Inhibition of mTOR using rapamycin induces mitochondria uncoupling in control rats, suggesting a role of mTOR as a moderator of mitochondria efficiency. No effect of mTOR inhibition was observed in mitochondria from diabetic animals, suggesting that there are other pathways in addition to the mTOR pathway regulating mitochondria function in diabetes. The functional significance of the mTOR pathway in regulating mitochondria efficiency warrants further attention.

  • 25.
    Stridh, Sara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Red Cross Univ Coll, Dept Hlth Sci, Stockholm, Sweden..
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Takahashi, Tomoko
    Hoshi Univ, Fac Pharmaceut Sci, Tokyo 1428501, Japan..
    Ikegami-Kawai, Mayumi
    Hoshi Univ, Fac Pharmaceut Sci, Tokyo 1428501, Japan..
    Friederich, Malou
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin2017Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 12, artikkel-id 2701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10−10 and 10−8 M) increased HA 3-fold. On the contrary, at a high concentration (10−6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling.

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