title: Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat.
abstract: TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, manifest hypertension, and exhibit increased tissue ANG II levels and oxidative stress. Evidence indicates that elevated tissue ANG II contributes to oxidative stress, increases in glomerular macromolecular permeability, and consequent albuminuria. Furthermore, angiotensin type 1 receptor (AT1R) blockers reduce albuminuria and slow progression of renal disease. However, it is not known whether improvements in glomerular filtration barrier integrity and albuminuria during treatment are related to reductions in oxidative stress and/or kidney renin-angiotensin system (RAS) activity. To investigate the renal protective effects of AT1R blockade, we treated young (6-7 wk old) male Ren2 rats with valsartan (Ren2-V; 30 mg/kg) for 3 wk and measured urine albumin, kidney malondialdehyde (MDA), RAS component mRNAs, and NADPH oxidase subunits (gp91(phox) and Rac1) compared with age-matched untreated Ren2 and Sprague-Dawley (S-D) rats. Basement membrane thickness, slit pore diameter and number, and foot process base width were measured by transmission electron microscopy (TEM). Results indicate that AT1R blockade lowered systolic blood pressure (30%), albuminuria (91%), and kidney MDA (80%) in Ren2-V compared with untreated Ren2 rats. Increased slit pore number and diameter and reductions in basement membrane thickness and podocyte foot process base width were strongly associated with albuminuria and significantly improved following AT1R blockade. AT1R blockade was also associated with increased angiotensin-converting enzyme-2 and neprilysin expression, demonstrating a beneficial shift in balance of renal RAS. Thus reductions in blood pressure, albuminuria, and tissue oxidative stress with AT1R blockade were associated with improved indexes of glomerular filtration barrier integrity and renal RAS in Ren2 rats.
authors.affiliation: Department of Internal Medicine, University of Missouri School of Medicine, 1 Hospital Dr., MA410 Medical Science Bldg., Columbia, MO 65212, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.forename: Nazif A
authors.initials: NA
authors.lastname: Chowdhury
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Craig S
authors.initials: CS
authors.lastname: Stump
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wiedmeyer
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gallagher
authors.forename: E Ann
authors.initials: EA
authors.lastname: Tallant
authors.forename: Shawna A
authors.initials: SA
authors.lastname: Cooper
authors.forename: C Daniel
authors.initials: CD
authors.lastname: Link
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrario
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D004195:Disease Models, Animal; D006977:Hypertension, Renal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D019255:NADPH Oxidases / Q000378:metabolism; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D012333:RNA, Messenger; D013777:Tetrazoles; D008315:Malondialdehyde; D000068756:Valsartan; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; D015260:Neprilysin; D014633:Valine