Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

Diabetic nephropathy is a major complication in type 2 diabetes mellitus and a leading cause of end-stage renal failure.1 The first sign of diabetic nephropathy is the appearance of albumin in the urine (microalbuminuria).2 Although the mechanisms underlying the occurrence of microalbuminuria in type 2 diabetes are extremely complex, the potential role of the renin-angiotensin system has been suggested.3,4,5,6,7,8,9,10,11 Large-scale clinical trials have shown that in hypertensive type 2 diabetic patients with microalbuminuria, lowering blood pressure by blockade of the renin-angiotensin system with angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors is more effective in reducing microalbuminuria than any other conventional antihypertensive therapies.3,4,5,6,7 These findings suggest that the antialbuminuric effects of renin-angiotensin system inhibition are independent of their blood pressure-lowering effects.12 Recently, the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study was conducted to examine if an ARB can prevent the onset of microalbuminuria.13 It has been demonstrated that early treatment with the ARB, olmesartan, significantly reduced the occurrence rate of microalbuminuria in type 2 diabetes patients.14 However, the precise mechanisms by which intensive Ang II blockade during a prediabetic state prevents the occurrence of microalbuminuria are not completely understood. A growing body of evidence has indicated that one of the most important mechanisms in the development of albuminuria is injury to glomerular epithelial cells (podocytes).15,16,17 Therefore, we hypothesized that the beneficial effect of an ARB on the onset of microalbuminuria is associated with its protective effect on podocyte injury. In particular, we aimed to characterize the mechanisms by which microalbuminuria develops in early type 2 diabetic nephropathy by focusing on the heterogeneity of glomerular podocyte abnormalities in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit pathological features of renal injury similar to those found in human type 2 diabetic patients with hypertension, obesity, and hyperinsulinemia.10,11,18,19,20