title: Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment.
abstract: Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22(phox)) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.
authors.affiliation: University of Missouri-Columbia School of Medicine, Department of Internal Medicine, Division of Nephrology, MA436, DC043.0, One Hospital Dr, Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
authors.forename: Shawna A
authors.initials: SA
authors.lastname: Cooper
authors.forename: Poorna R
authors.initials: PR
authors.lastname: Karuparthi
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Nathan
authors.initials: N
authors.lastname: Rehmer
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Andresen
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000419:Albuminuria / Q000503:physiopathology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002461:Cell Line, Transformed; D004789:Enzyme Activation / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D050199:Podocytes / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C473112:Ren2 protein, mouse; D013449:Sulfonamides; D000804:Angiotensin II; D000068718:Rosuvastatin Calcium; D019255:NADPH Oxidases; D012083:Renin