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  • 1.
    Bamberg, Krister
    et al.
    AstraZeneca, BioPharmaceut R&D, Translat Sci & Expt Med, Res & Early Dev,Cardiovasc Renal & Metab, Gothenburg, Sweden..
    William-Olsson, Lena
    AstraZeneca, BioPharmaceut R&D, Biosci Renal Res & Early Dev, Cardiovasc Renal & Metab, Gothenburg, Sweden..
    Johansson, Ulrika
    AstraZeneca, BioPharmaceut R&D, Biosci Renal Res & Early Dev, Cardiovasc Renal & Metab, Gothenburg, Sweden..
    Arner, Anders
    Lund Univ, Dept Clin Sci Lund, Lund, Sweden..
    Hartleib-Geschwindner, Judith
    AstraZeneca, BioPharmaceut R&D, Projects Res & Early Dev, Cardiovasc Renal & Metab, Gothenburg, Sweden..
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption2020In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 125, no 4, p. 274-280Article in journal (Refereed)
    Abstract [en]

    Background The most profound effect of vasopressin on the kidney is to increase water reabsorption through V-2-receptor (V2R) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of V2R stimulation on kidney function, isolated from systemic effects. Methods The role of V2R in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula. Results Kidneys subjected to V2R stimulation using desmopressin (DDAVP) displayed stable osmolality and calcium reabsorption throughout the experiment, whereas kidneys not administered DDAVP exhibited a simultaneous fall in urine osmolality and calcium reabsorption. Epithelial sodium channel (ENaC) inhibition using amiloride resulted in a marked increase in potassium reabsorption along with decreased sodium reabsorption. Conclusions A stable isolated perfused kidney model with computer-controlled pressure regulation was developed, which retained key physiological functions. The preparation responds to pharmacological inhibition of ENaC channels and activation of V2R. Using the model, the dynamic effects of V2R stimulation on calcium handling and urine osmolality could be visualised. The study thereby provides evidence for a stimulatory role of V2R in renal calcium reabsorption.

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  • 2.
    Brown, Russell D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Thorén, Peter
    Steege, Andreas
    Mrowka, Ralf
    Sällström, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Skøtt, Ole
    Fredholm, Bertil B
    Persson, A Erik G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Influence of the adenosine A1 receptor on blood pressure regulation and renin release.2006In: Am J Physiol Regul Integr Comp Physiol, ISSN 0363-6119, Vol. 290, no 5, p. R1324-9Article in journal (Other scientific)
  • 3.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Brown, Russell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Edlund, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Teerlink, Tom
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals2008In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 294, no 2, p. 362-370Article in journal (Refereed)
    Abstract [en]

    Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.

  • 4.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Skott, Ole
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Uninephrectomy in Young Age or Chronic Salt Loading Causes Salt-Sensitive Hypertension in Adult Rats2007In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 49, no 6, p. 1342-1350Article in journal (Refereed)
    Abstract [en]

    The importance of nephron endowment and salt intake for the development of hypertension is under debate. The present study was designed to investigate whether reduced nephron number, after completion of nephrogenesis, or chronic salt loading causes renal injury and salt-sensitive hypertension in adulthood. Rats were operated at 3 weeks of age (after completed nephrogenesis) and then subjected to either normal or high-salt diets for 6 to 8 weeks. Four different experimental groups were used: sham-operated animals raised with normal-salt diet (controls) or high-salt diet (HS) and uninephrectomized animals raised with normal-salt diet (UNX) or high-salt diet (UNX+HS). In the adult animals, renal and cardiovascular functions were evaluated and blood pressure recorded telemetrically under different sodium conditions (normal, high, and low). Hypertension was present in UNX+HS (122±9 mm Hg), UNX (101±3 mm Hg), and HS (96± 1 mm Hg) groups on normal-salt diets compared with the controls (84±2 mm Hg), and the blood pressure was salt sensitive (high- versus normal-salt diet; 23±3, 9±2, 7±2, and 1±1 mm Hg, respectively). The hypertensive groups (UNX+HS, UNX, and HS) had increased diuresis and reduced ability to concentrate urine. The glomerular filtration rate (milliliters per minute) in anesthetized rats was reduced in the UNX+HS (2.36±0.30) and UNX animals (2.00±0.31) compared with both HS animals (3.55±0.45) and controls (3.01±0.35). Hypertensive groups displayed reduced plasma renin concentrations during high sodium conditions and hypertrophic kidneys and hearts with various degrees of histopathologic changes. In conclusion, at a young age after completed nephrogenesis, uninephrectomy or chronic salt loading causes renal and cardiovascular injury with salt-sensitive hypertension.

  • 5.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Skott, Ole
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt-sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt-sensitive hypertension.

    Methods: PUUO was created in 3-week-old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated.

    Results: All hydronephrotic animals developed salt-sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes.

    Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt-sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.

  • 6.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Patzak, Andreas
    Sendeski, Mauricio
    Scheffer, Peter G.
    Teerlink, Tom
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fredholm, Bertil B.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Adenosine A(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment2011In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 6, p. R1669-R1681Article in journal (Refereed)
    Abstract [en]

    Adenosine mediates tubuloglomerular feedback responses via activation of A(1)-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A(1)-receptor knockout (A(1)(-/-)) and wild-type (A(1)(+/+)) mice we investigated the hypothesis that A(1)-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or ANG II treatment. The hypertensive responses to L-NAME and ANG II were clearly attenuated in A(1)(-/-) mice. Arteriolar contractions to L-NAME (10(-4) mol/l; 15 min) and cumulative ANG II application (10(-12) to 10(-6) mol/l) were lower in A(1)(-/-) mice. Simultaneous treatment with tempol (10(-4) mol/l; 15 min) attenuated arteriolar responses in A(1)(+/+) but not in A(1)(-/-) mice, suggesting differences in ROS formation. Chronic treatment with L-NAME or ANG II did not alter arteriolar responses in A(1)(-/-) mice, but enhanced maximal contractions in A(1)(+/+) mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A(1)(+/+) mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A(1)-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A(1)-receptor signaling blunts L-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.

  • 7.
    Luft, Friedrich C.
    et al.
    Charite Med Fac, Expt & Clin Res Ctr, Berlin, Germany..
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Amiloride and calciuria2022In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 37, no 2, p. 205-207Article in journal (Other academic)
  • 8.
    Schnermann, Jurgen
    et al.
    NIH, NIDDK, Bldg 10, Bethesda, MD 20892 USA..
    Carlstrom, Mattias
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    BIbliographical item: OBITUARY Erik Persson (1941-2020) - a Remembrance. In ACTA PHYSIOLOGICA Volume: 230 Issue: 4 Article Number: e135682020Other (Other academic)
  • 9.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Functional Aspects of the Juxtaglomerular Apparatus: Control of Glomerular Filtration and Renin Release2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The juxtaglomerular apparatus (JGA) is a control unit of the kidney, that regulates glomerular filtration rate (GFR) and renin release, and hence extracellular volume and blood pressure. The tubuloglomerular feedback (TGF) mechanism is a negative feedback loop that regulates GFR. Neuronal nitric oxide synthase (nNOS) is highly expressed in the macula densa cells of the JGA, and regulates the sensitivity of the TGF mechanism. Hypertension has been proposed to be caused by an increased sensitivity of the TGF due to nNOS deficiency. In diabetes, reduced TGF activity due to increased sodium-glucose reabsorption is suggested to cause hyperfiltration. Glomerular hyperfiltration has clinical significance, since it correlates with the risk of developing nephropathy.

    In this thesis, the role of nNOS in the control of blood pressure and renin release was investigated in nNOS knockout mice (nNOS-/-) treated with low- and high sodium diets. The nNOS-/- were normotensive, but displayed an impaired renin regulation, and failed to increase renin in response to a low sodium diet. A significantly larger renin increase during phosphodiesterase 3 (PDE3) inhibition was found in nNOS-/- compared to the wild types, resulting in similar renin levels.

    Furthermore, the role of TGF and proximal glucose reabsorption in diabetes-induced hyperfiltration was investigated in adenosine A1-receptor knockout mice (A1AR-/-) that are known to lack a functional TGF mechanism. Diabetes was induced in A1AR-/- and wild types by injection of alloxan. The diabetic A1AR-/- displayed a similar degree of hyperfiltration as their wild-type controls. Inhibition of renal sodium-glucose transporters reduced GFR in both genotypes, but the reduction was even more pronounced in the A1AR-/-.

    In conclusion, the results indicate that renin secretion during low sodium conditions is mediated by nNOS-derived nitric oxide via cGMP-mediated inhibition of PDE3, whereas deletion of the nNOS gene does not cause hypertension. Diabetes-induced hyperfiltration is not mediated by TGF, but appears to be dependent on increased renal glucose reabsorption.

    List of papers
    1. Neuronal nitric oxide synthase-deficient mice have impaired renin release but normal blood pressure
    Open this publication in new window or tab >>Neuronal nitric oxide synthase-deficient mice have impaired renin release but normal blood pressure
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    2008 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, no 1, p. 111-116Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Nitric oxide deficiency is involved in the development of hypertension, but the mechanisms are currently unclear. This study was conducted to further elucidate the role of neuronal nitric oxide synthase (nNOS) in blood pressure regulation and renin release in relation to different sodium loads. METHODS: Blood pressure and heart rate were measured telemetrically and assessed during periods of physical activity and inactivity. Urinary solute excretion was measured by metabolism cages and plasma renin concentration (PRC) was determined by radioimmunoassay; all in nNOS knockout (nNOS(-/-)) and wild-type (nNOS(+/+)) mice after 10 days of low (0.01% NaCl) and high (4% NaCl) sodium diets. RESULTS: The resting heart rate was reduced in nNOS(-/-) mice, but the two genotypes had similar blood pressure during the low (nNOS(+/+) 104 +/- 2 mm Hg; nNOS(-/-) 103 +/- 2 mm Hg) and high (nNOS(+/+) 107 +/- 3 mm Hg; nNOS(-/-) 108 +/- 2 mm Hg) sodium diets. During the high sodium diet, PRC did not differ between the genotypes (nNOS(+/+) 743 +/- 115 10(-5) Goldblatt units; nNOS(-/-) 822 +/- 63 10(-5) Goldblatt units), but during the low sodium diet, nNOS(-/-) mice failed to increase PRC (nNOS(+/+) 2164 +/- 220 10(-5) Goldblatt units; nNOS(-/-) 907 +/- 101 10(-5) Goldblatt units) and renal renin mRNA. On the low sodium diet, nNOS(-/-) mice also showed increased urine flow rate and osmolar excretion, observations not made during a high sodium diet. CONCLUSIONS: Our results show that nNOS is necessary for stimulation of renin in response to sodium restriction. Furthermore, nNOS(-/-) mice are normotensive, and their blood pressure responds normally to an increased dietary sodium intake, indicating that nNOS deficiency does not cause salt-sensitive hypertension.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-104335 (URN)10.1038/ajh.2007.16 (DOI)000251938200027 ()18091753 (PubMedID)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2022-01-28Bibliographically approved
    2. Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 3
    Open this publication in new window or tab >>Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 3
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    2010 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 23, no 11, p. 1241-1246Article in journal (Refereed) Published
    Abstract [en]

    Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells.

    Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3.

    Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively.

    Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.

    Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-113177 (URN)10.1038/ajh.2010.153 (DOI)000283531900016 ()
    Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2022-01-28Bibliographically approved
    3. Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism
    Open this publication in new window or tab >>Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism
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    2007 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 190, no 3, p. 253-259Article in journal (Refereed) Published
    Abstract [en]

    Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism.

    Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated.

    Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes.

    Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area.

    Keywords
    adenosine, diabetes mellitus, glomerular hyperfiltration, tubuloglomerular feedback
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-11928 (URN)10.1111/j.1748-1716.2007.01705.x (DOI)000247318600008 ()17581137 (PubMedID)
    Available from: 2007-11-07 Created: 2007-11-07 Last updated: 2017-12-11Bibliographically approved
    4. Inhibition of sodium-linked glucose reabsorption in the kidney normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor-deficient mice
    Open this publication in new window or tab >>Inhibition of sodium-linked glucose reabsorption in the kidney normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor-deficient mice
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    2014 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 210, no 2, p. 440-445Article in journal (Refereed) Published
    Abstract [en]

    Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. In this study, we investigated the role of the increased tubular sodium/glucose co-transport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback mechanism (TGF), we used adenosine A1-receptor deficient (A1AR-/-) mice known to lack a functional TGF mechanism, and compared the results to corresponding wild-type animals (A1AR+/+). Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose co-transporters were inhibited by phlorizin 30 minutes prior to GFR measurements. Normoglycemic animals had a similar GFR independent of genotype, and induction of diabetes resulted in similar glomerular hyperfiltration in both groups. Phlorizin had no effect on GFR in normoglycemic mice, whereas it reduced GFR in both genotypes during diabetes. Notably, the reduction was more pronounced in the A1AR-/-. This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-113176 (URN)10.1111/apha.12152 (DOI)000329519500020 ()
    Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2017-12-12Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 10.
    Sällström, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    The Effect of Nitric Oxide and Tubuloglomerular Feedback on Renin Release and Diabetes Induced Hyperfiltration2007Licentiate thesis, monograph (Other scientific)
  • 11.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fredholm, Bertil B
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 190, no 3, p. 253-259Article in journal (Refereed)
    Abstract [en]

    Aims: Glomerular hyperfiltration is commonly found in diabetic patients early after the onset of disease. This is one of the first indications of the development of progressive diabetic nephropathy. It has been proposed that glomerular hyperfiltration is caused by decreased delivery of electrolytes to the macula densa due to the increased sodium and glucose reabsorption in the proximal tubule, which would increase the glomerular filtration rate (GFR) via the tubuloglomerular feedback (TGF) mechanism. In this study, we investigated the role of TGF in diabetes-induced glomerular hyperfiltration by inducing diabetes in adenosine A1-receptor knockout (A1AR−/−) mice known to lack a functional TGF mechanism.

    Methods: Diabetes was induced by alloxan (75 mg kg−1 bw) injected into the tail vein. The 24-hour urinary electrolyte excretion was measured in metabolic cages, the GFR determined by inulin clearance under isoflurane-anaesthesia, and histological changes evaluated.

    Results: All alloxan-treated animals developed hyperglycaemia (≥20 mm). Normoglycaemic animals had a similar GFR independent of genotype (A1AR+/+ 9.3 ± 0.5 vs. A1AR−/− 10.1 ± 0.8 μL min−1g−1 bw) and diabetes resulted in similar glomerular hyperfiltration in both groups (A1AR+/+ 14.0 ± 1.7, n = 9 vs. A1AR−/− 15.3 ± 1.9 μL min−1g−1 bw). Diabetic animals had a similar tendency to develop interstitial fibrosis, whereas the glomerular volume was similar in both genotypes, and unaltered by diabetes.

    Conclusions: This study shows that the A1AR−/− mice develop diabetes-induced glomerular hyperfiltration, demonstrating that the TGF mechanism is not the major cause of the development of hyperfiltration. Furthermore, the hyperfiltration in the present study was not related to alterations in the glomerular filtration area.

  • 12.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simultaneous determination of renal plasma flow and glomerular filtration rate in conscious mice using dual bolus injection2013In: Journal of pharmacological and toxicological methods, ISSN 1056-8719, E-ISSN 1873-488X, Vol. 67, no 3, p. 187-193Article in journal (Refereed)
    Abstract [en]

    Introduction: The present report describes and evaluates a simple protocol for serial measurements of glomerular filtration rate (GFR) and renal plasma flow (RPF) in conscious mice. Methods: In conscious mice, a bolus of [H-3] methoxy-inulin and [C-14] para-amino-hippuric (PAH) was injected in the tail vein whereupon eight blood samples were taken during the following 75 min. Plasma concentrations were determined by liquid scintillation and clearances of the injected markers were calculated by non-compartmental pharmacokinetic data analysis of the plasma disappearance curves. In anaesthetized mice, the renal extraction ratio of PAH was determined by infusion of PAH and subsequent analysis of blood taken from the carotid artery and the renal vein. The acquired value (0.70 +/- 0.02) was used for all subsequent calculations of RPF. To evaluate the protocol, a crossover study was performed where either the vehicle or the angiotensin II AT1 receptor antagonist candesartan was given prior to the clearance measurements. Results: Baseline values of GFR and RPF were in line with those earlier reported in mice. Administration of candesartan increased RPF and reduced the filtration fraction, whereas GFR was unaltered. These changes are supported by earlier findings and demonstrate that GFR and RPF can be determined independently. Furthermore, modelling experiments demonstrated that acceptable results are obtained even if the number of blood samples is reduced to four which is a way to further simplify the procedure. Discussion: The method provides an effective way for repeated measurements of GFR and RPF in mice without potentially confounding effects of anaesthesia.

  • 13.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gao, Xiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nilsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Jensen, Boye L.
    Onozato, Maristela L.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension2013In: AM J PHYSIOL-RENAL, ISSN 1931-857X, Vol. 305, no 1, p. F71-F79Article in journal (Refereed)
    Abstract [en]

    Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein (EphA4(gf/gf)), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4(gf/gf) mice and littermate controls (EphA4(+/+)) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4(gf/gf) mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4(+/+), the EphA4(gf/gf) mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4(gf/gf) mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans.

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