Valsartan slows the progression of diabetic nephropathy in db/db mice via reduction in podocyte injury and renal oxidative stress and inflammation

This study sought to determine whether doses of angiotensin II receptor blocker (ARB) that maximally reduce proteinuria could slow the progression of glomerulosclerosis in the uninephrectomized db/db mouse, a model of type 2 diabetes. Untreated uninephrectomized db/db mice had normal blood pressure but developed progressive albuminuria and mesangial matrix expansion between weeks 18 and 22, associated with increased renal expression of TGFß1, PAI-1, type IV collagen and fibronectin. Treatment with valsartan in drinking water from weeks 18 to 22 at a dose that maximally reduced proteinuria determined previously prevented the increases in albuminuria and markers of renal fibrosis seen in db/db mice. In addition, WT-1 immunopositive podocyte numbers were found to be lower in the untreated diabetic glomeruli. The expression of podocin and nephrin was continually decreased in diabetes between weeks 18 and 22. Valsartan administration substantially ameliorated these changes that are indicative of podocyte injury. Renal expressions of TNF-α, MCP-1, Nox2, p22phox and p47phox and urine TBARS levels, the markers of renal inflammation and oxidative stress, were increased during disease progression in diabetic mice. Valsartan treatment reduced these markers. Thus, high dose of valsartan not only reduces albuminuria maximally but also halts the progression of glomerulosclerosis resulting from type 2 diabetes via reduction in podocyte injury and renal oxidative stress and inf...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research