Abstract
In the present study, we tested whether polycystic kidney disease (PKD) is associated with renal tissue hypoxia and oxidative stress, which, in turn, contribute to the progression of cystic disease and hypertension. Lewis polycystic kidney (LPK) rats and Lewis control (Lewis) rats were treated with tempol (1 mmol/L in drinking water) from 3 to 13 weeks of age or remained untreated. The LPK rats developed polyuria, uraemia and proteinuria. At 13 weeks of age, LPK rats had greater mean arterial pressure (1.5-fold), kidney weight (sixfold) and plasma creatinine (3.5-fold) than Lewis rats. Kidneys from LPK rats were cystic and fibrotic. Renal hypoxia was evidenced by staining for pimonidazole adducts and hypoxia-inducible factor (HIF)-1α in cells lining renal cysts and upregulation of HIF-1α and its downstream targets vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1) and heme oxygenase 1 (HO-1). However, total HO activity did not differ greatly between kidney tissue from LPK compared with Lewis rats. Renal oxidative and/or nitrosative stress was evidenced by ninefold greater immunofluorescence for 3-nitrotyrosine in kidney tissue from LPK compared with Lewis rats and a > 10-fold upregulation of mRNA for p47phox and gp91phox. Total renal superoxide dismutase (SOD) activity was sevenfold less and expression of SOD1 mRNA was 70% less in kidney tissue from LPK compared with Lewis rats. In LPK rats, tempol treatment reduced immunofluorescence for 3-nitrotyrosine and HIF1A mRNA while upregulating VEGF and p47phox mRNA expression, but otherwise had little impact on disease progression, renal tissue hypoxia or hypertension. Our findings do not support the hypothesis that oxidative stress drives hypoxia and disease progression in PKD.
© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arterial Pressure / drug effects
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Arterial Pressure / genetics
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Cell Hypoxia / drug effects
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Creatinine / blood
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Cyclic N-Oxides / pharmacology*
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Disease Progression
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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Heme Oxygenase (Decyclizing) / genetics
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Heme Oxygenase (Decyclizing) / metabolism
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Hemodynamics / drug effects
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Hemodynamics / genetics
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Hypertension / drug therapy
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Hypertension / genetics
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Hypertension / metabolism
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Hypertension / pathology
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Kidney / drug effects
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Kidney / metabolism
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Kidney / pathology
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Kidney Diseases / drug therapy*
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Kidney Diseases / genetics
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Kidney Diseases / metabolism
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Kidney Diseases / pathology*
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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NADPH Oxidase 2
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Oxidative Stress / drug effects
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Oxidative Stress / genetics
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Polycystic Kidney Diseases / drug therapy*
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Polycystic Kidney Diseases / genetics
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Polycystic Kidney Diseases / metabolism
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Polycystic Kidney Diseases / pathology*
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Rats
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Rats, Inbred Lew
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Spin Labels
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Tyrosine / analogs & derivatives
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Tyrosine / genetics
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Tyrosine / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Cyclic N-Oxides
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Glucose Transporter Type 1
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Glycoproteins
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Spin Labels
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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3-nitrotyrosine
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Tyrosine
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Creatinine
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Heme Oxygenase (Decyclizing)
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Hmox1 protein, rat
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Sod1 protein, rat
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Superoxide Dismutase
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Superoxide Dismutase-1
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Cybb protein, rat
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NADPH Oxidase 2
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NADPH Oxidases
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neutrophil cytosolic factor 1
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tempol