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Nordquist, Lina
Publications (10 of 38) Show all publications
Nordquist, L., Friederich-Persson, M., Fasching, A., Liss, P., Shoji, K., Nangaku, M., . . . Palm, F. (2015). Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy. Journal of the American Society of Nephrology, 26(2), 328-338
Open this publication in new window or tab >>Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
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2015 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 26, no 2, p. 328-338Article in journal (Refereed) Published
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.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-232171 (URN)10.1681/ASN.2013090990 (DOI)000348623700012 ()25183809 (PubMedID)
Available from: 2014-09-15 Created: 2014-09-15 Last updated: 2017-12-05Bibliographically approved
Carlsson, A. C., Nordquist, L., Larsson, T. E., Carrero, J.-J., Larsson, A., Lind, L. & Ärnlöv, J. (2015). Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals. Cardiorenal Medicine, 5(4), 278-288
Open this publication in new window or tab >>Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals
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2015 (English)In: Cardiorenal Medicine, ISSN 1664-3828, Vol. 5, no 4, p. 278-288Article in journal (Refereed) Published
Abstract [en]

Objective: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes. Research Design and Methods: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as >= 60, 30-60, and = 60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes. Conclusions: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings.

Keywords
Community, TNF-alpha, Glomerular filtration, Albumin/creatinine ratio, Chronic kidney disease, Inflammation
National Category
Urology and Nephrology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-259538 (URN)10.1159/000435863 (DOI)000363827900005 ()26648944 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2015-08-08 Created: 2015-08-08 Last updated: 2017-04-04Bibliographically approved
Friederich-Persson, M., Welch, W. J., Luo, Z., Palm, F. & Nordquist, L. (2014). Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells. Paper presented at 41st Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT), JUN 22-26, 2013, Hanover, NH. Advances in Experimental Medicine and Biology, 812, 157-163
Open this publication in new window or tab >>Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells
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2014 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 157-163Article in journal (Refereed) Published
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).

Keywords
Proximal tubule cell, Oxidative stress, Angiotensin-II, Oxygen consumption, Electrolyte transport
National Category
Respiratory Medicine and Allergy Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-240034 (URN)10.1007/978-1-4939-0620-8_21 (DOI)000345121200022 ()24729228 (PubMedID)978-1-4939-0620-8 (ISBN)978-1-4939-0583-6 (ISBN)
Conference
41st Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT), JUN 22-26, 2013, Hanover, NH
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2018-01-11
Hultström, M., Roxhed, N. & Nordquist, L. (2014). Intradermal Insulin Delivery: A Promising Future for Diabetes Management. Journal of Diabetes Science and Technology, 8(3), 453-457
Open this publication in new window or tab >>Intradermal Insulin Delivery: A Promising Future for Diabetes Management
2014 (English)In: Journal of Diabetes Science and Technology, E-ISSN 1932-2968, Vol. 8, no 3, p. 453-457Article in journal (Refereed) Published
Abstract [en]

The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-227622 (URN)10.1177/1932296814530060 (DOI)24876605 (PubMedID)
Available from: 2014-06-29 Created: 2014-06-29 Last updated: 2018-01-18Bibliographically approved
Pihl, L., Nangaku, M., Inagi, R., Liss, P., Palm, F. & Nordquist, L. (2014). Pre-existing hypoxia sensitizes the kidney to an ischemia-reperfusion insult. Paper presented at EXPERIMENTAL BIOLOGY 2014 - Transforming the Future through Science, EB, April 26-30, 2014, Sand Diego, USA. The FASEB Journal, 28(1), Article ID 890.10.
Open this publication in new window or tab >>Pre-existing hypoxia sensitizes the kidney to an ischemia-reperfusion insult
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2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 890.10Article in journal, Meeting abstract (Other academic) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-246755 (URN)000346651003211 ()
Conference
EXPERIMENTAL BIOLOGY 2014 - Transforming the Future through Science, EB, April 26-30, 2014, Sand Diego, USA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
Nordquist, L., Liss, P., Fasching, A., Hansell, P. & Palm, F. (2013). Hypoxia in the diabetic kidney is independent of advanced glycation end-products. Advances in Experimental Medicine and Biology, 765, 185-193
Open this publication in new window or tab >>Hypoxia in the diabetic kidney is independent of advanced glycation end-products
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2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 185-193Article in journal (Refereed) Published
Abstract [en]

Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N6-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO2) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO2 and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-182297 (URN)10.1007/978-1-4614-4989-8_26 (DOI)000339280100027 ()22879032 (PubMedID)
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2018-01-12Bibliographically approved
Friederich-Persson, M., Persson, P., Fasching, A., Hansell, P., Nordquist, L. & Palm, F. (2013). Increased kidney metabolismas a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats. Paper presented at 40th Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT), AUG 19-24, 2012, Bruges, BELGIUM. Advances in Experimental Medicine and Biology, 789, 9-14
Open this publication in new window or tab >>Increased kidney metabolismas a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats
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2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 789, p. 9-14Article in journal (Refereed) Published
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.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-220245 (URN)10.1007/978-1-4614-7411-1_2 (DOI)000343662700003 ()23852470 (PubMedID)978-1-4614-7411-1 (ISBN)978-1-4614-7256-8 (ISBN)
Conference
40th Annual Meeting of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT), AUG 19-24, 2012, Bruges, BELGIUM
Available from: 2014-03-12 Created: 2014-03-12 Last updated: 2018-01-11
Singh, P., Ricksten, S.-E., Bragadottir, G., Redfors, B. & Nordquist, L. (2013). Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clinical and experimental pharmacology & physiology, 40(2), 138-147
Open this publication in new window or tab >>Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease
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2013 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 138-147Article, review/survey (Refereed) Published
Abstract [en]

Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.

Keywords
acute kidney injury, chronic kidney disease, glomerular filtration rate, nitric oxide, oxygen consumption, oxygenation, renal blood flow
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-196138 (URN)10.1111/1440-1681.12036 (DOI)000314244300010 ()
Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06Bibliographically approved
Friederich Persson, M., Aslam, S., Nordquist, L., Welch, W. J., Wilcox, C. S. & Palm, F. (2012). Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys. PLoS ONE, 7(7), e39635
Open this publication in new window or tab >>Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed) 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.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-167782 (URN)10.1371/journal.pone.0039635 (DOI)000305966500017 ()
Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2018-01-12Bibliographically approved
Lindahl, E., Nordquist, L., Müller, P., El Agha, E., Friederich, M., Dahlman-Wright, K., . . . Jörnvall, H. (2011). Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells. Diabetes/Metabolism Research Reviews, 27(7), 697-704
Open this publication in new window or tab >>Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells
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2011 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 27, no 7, p. 697-704Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-160915 (URN)10.1002/dmrr.1220 (DOI)000300106100009 ()21618400 (PubMedID)
Available from: 2011-11-03 Created: 2011-11-03 Last updated: 2017-12-08Bibliographically approved
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