title: Chronic treatment with tempol does not significantly ameliorate renal tissue hypoxia or disease progression in a rodent model of polycystic kidney disease.
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.
authors.affiliation: The Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Alice
authors.initials: A
authors.lastname: Ding
authors.forename: Priyadharshani
authors.initials: P
authors.lastname: Kalaignanasundaram
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.forename: Amany
authors.initials: A
authors.lastname: Abdelkader
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Brad R S
authors.initials: BR
authors.lastname: Broughton
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Kim
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Wyse
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Phillips
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D018450:Disease Progression; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects / Q000235:genetics; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014443:Tyrosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D013113:Spin Labels; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C002744:3-nitrotyrosine; D014443:Tyrosine; D003404:Creatinine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C001803:tempol