Insulin Resistance, Oxidative Stress, and Podocyte Injury: Role of Rosuvastatin Modulation of Filtration Barrier Injury

Abstract

Background/Aim: There is an emerging relationship between insulin resistance/hyperinsulinemia, oxidative stress, and glomerular injury manifesting as albuminuria. HMG-CoA reductase inhibitors (statins) have been shown to reduce oxidative stress in the vasculature as well as albuminuria in animal models and in human studies. The glomerular filtration barrier is emerging as a critical determinant of albumin filtration. We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier. Method: Young Zucker obese and Zucker lean rats (6–7 weeks old) were treated with the HMG-CoA reductase inhibitor rosuvastatin (10 mg/kg/day) or placebo for 21 days. Results: In the Zucker obese rats, homeostasis model assessment-insulin resistance index, oxidative markers (NADPH oxidase activity, reactive oxygen species, and urine isoprostane formation), podocyte foot process effacement, and albuminuria were increased as compared with Zucker lean controls, independent of increases in systolic blood pressure. Albuminuria correlated with podocyte foot process effacement (r² = 0.61) and insulin level (r² = 0.69). Rosuvastatin treatment improved albuminuria, filtration barrier indices, and oxidative stress via copper/zinc superoxide dismutase. Conclusions: These data indicate that hyperinsulinemia together with insulin resistance is associated with podocyte injury and albuminuria independent of the systolic blood pressure. Further, rosuvastatin modulates filtration barrier injury and albuminuria and improves oxidative stress measures via copper/zinc superoxide dismutase.

A Trial of Pitavastatin Versus Rosuvastatin for Dyslipidemia in Chronic Kidney Disease

“…Some other basic studies also suggest that the renoprotective effects of statins are mediated via the antiinflammatory, vascular endothelial function-improving, antioxidant activities, etc. ; this proposal is in line with the suggested mechanisms of renoprotection mentioned above [23][24][25] . Many available clinical data also suggest the renoprotective effects of statins, thereby supporting the validity of results from the present study [26][27][28] .…”

Redox Control of Renal Function and Hypertension

“…Elevated tissue RAAS has been shown to increase oxidative stress in these animals, contributing to insulin resistance, hypertension, and proteinuria. Existing work in the heart, aorta, and kidney established Ang II as a key mediator of tissue inflammation, oxidative stress, and remodeling (75,174,218,261,287,334,346,347,(351)(352)(353)(354)(355). Work from our laboratory and others indicated a role for Ang II production of ROS in the kidney by stimulating NAD(P)H oxidase and subunits, including p47 phox , p67 phox , and Rac1 (355).…”

Low Aerobic Capacity and High-Fat Diet Contribute to Oxidative Stress and IRS-1 Degradation in the Kidney

“…7.5) containing protease (Complete; Roche Diagnostics, Mannheim, Germany) and phosphatase inhibitors (Cocktail-1 and Cocktail-2; Sigma). The tissue was homogenized and cellular fractionation was performed as previously described [22,23,24]. Briefly, approximately 400–500 mg of tissue was homogenized in a Dounce glass-on-glass homogenizer.…”

“…The formation of ROS was evaluated in kidney tissue by lucigenin-enhanced chemiluminescence, as previously described [23]. Kidney tissue whole homogenate (100 µl) was added to 1.4 ml of 50 m M phosphate (KH 2 PO 4 ) buffer (150 m M sucrose, 1 m M EGTA, 5 µ M lucigenin, 100 µ M NADPH, pH 7.0) in dark-adapted counting vials.…”