Diabetic Nephropathy

Mechanisms

At a symposium on the development of diabetic nephropathy, Erwin Böttinger (New York, NY) discussed the molecular pathology of diabetic nephropathy in mice and men, referring to the growing problems of chronic kidney disease (CKD) due to diabetes. The U.S. prevalence of CKD is predicted to increase from ∼340,000 persons in 2000 to 660,000 in 2010, with annual cost increasing from ∼15 to 30 billion dollars. Diabetes differs from other causes of CKD in its predictability, with well-defined functional progression from hyperfiltration to micro- to macroalbuminuria to renal failure. The morphologic findings of glomerular basement membrane (GBM) thickening, mesangial expansion, arteriolar hyalinosis, glomerulosclerosis, and tubulo-interstitial fibrosis are well recognized. Böttinger termed the cellular substrate of diabetic nephropathy, however, “much less clear,” with podocyte depletion, which appears to be a reproducible early finding, appearing to be crucial to disease pathogenesis. Podocytes are glomerular epithelial cells essential for glomerular structure and function, surrounding glomerular capillaries and forming foot processes contributing to the filtration barrier and providing structural stabilization. Podocyte depletion in human diabetic nephropathy may be a genetic trait (independent of diabetes), may be caused by detachment from the basement membrane due to the disease process, or may be caused by apoptosis or necrosis.

In mouse models of type 1 (streptozotocin [STZ]) and type 2 (db/db) diabetes, hyperglycemia predictably leads to development of albuminuria. Podocyte loss is seen after onset of hyperglycemia and precedes the onset of albuminuria, with podocyte apoptosis coinciding with the onset of hyperglycemia, again preceding albuminuria. Endocapillary apoptosis is not observed in these models. In cell culture, there is a dose response between ambient glucose and the degree of podocyte apoptosis, suggesting a mechanism for …