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.
Microalbuminuria is a simple screening test that is not only associated with an increased risk of progressive renal insufficiency, but also an increased risk of cardiovascular disease and stroke in the cardiometabolic syndrome. The role of oxidative stress, inflammation, and cellular-extracellular matrix remodeling fibrosis is very important, and the authors have previously observed that albuminuria is related, in part, to loss of the integrity of the glomerular filtration apparatus. The proximal tubule may play a more important role than previously thought, as it is estimated that in health this portion of the nephron reabsorbs 5-8 g of albumin that normally leaks through the glomerulus on a daily basis. Recently, the authors have made important preliminary observational findings regarding proximal tubule microvilli remodeling and oxidative stress, which may help to explain microalbuminuria. These observations suggest that albuminuria is associated with proximal tubule injury, as well as loss of integrity of the glomerular filtration barrier in association with obesity and insulin resistance.
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