Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat.
TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5-8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT(1)R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6-7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-beta-D-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and x60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats (P < 0.05) correlated strongly with albuminuria (r(2) = 0.83) and moderately with MDA (r(2) = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats (P < 0.05). AT(1)R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-beta-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.
Hayden
Melvin R
MR
Department of Internal Medicine, University of Missouri, Columbia, USA.
Chowdhury
Nazif A
NA
Cooper
Shawna A
SA
Whaley-Connell
Adam
A
Habibi
Javad
J
Witte
Lauren
L
Wiedmeyer
Charles
C
Manrique
Camila Margarita
CM
Lastra
Guido
G
Ferrario
Carlos
C
Stump
Craig
C
Sowers
James R
JR
D000118:Acetylglucosaminidase / Q000378:metabolism; D000419:Albuminuria / Q000503:physiopathology*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D007687:Kidney Tubules, Proximal / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D046529:Microscopy, Electron, Transmission; D008871:Microvilli / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D008315:Malondialdehyde; D000118:Acetylglucosaminidase