Evidence For Role Of Tgfp In Diabetic Nephropathy

Koch's postulates have classically been used to determine whether an agent is the cause of an infectious disease, but the paradigm can be adapted to ascertain the role of TGF-P in DN (1). If TGF-P is a causative agent, then it should be found in diabetic kidneys in increased levels. TGF-P has been shown to be elevated intrarenally in human DN (2-5) and in experimental animal models of diabetic renal disease, at both the mRNA and protein levels, and in both the glomerular and tubulo-interstitial compartments (6-9). Increased amounts of TGF-P1 (one of the three mammalian isoforms of TGF-P) are also excreted in the urine of diabetic patients (10-12). The kidney in diabetes can also be a source of TGF-P. When the TGF-P1 mass balance was calculated across the renal vascular bed (in patients undergoing cardiac catheterization), it was estimated that nondiabetic kidneys were extracting TGF-P1 from the circulation whereas diabetic kidneys were adding TGF-P1 to the bloodstream (13).

If TGF-P contributes to DN, the increase in renal TGF-P should be attributable to the diabetic state. High glucose, elevated angiotensin II, amadori-modified proteins, advanced glycation endproducts, thromboxane, endothelin, platelet-derived growth factor, and leptin have all been shown to stimulate TGF-P production by cultured renal cells, which include mesangial, proximal tubular, interstitial fibroblast, and glomerular endothelial cells (14-22). In humans with type 2 diabetes, the degree of glycemic control correlates with the increase in glomerular expression of TGF-P1 (2). Even in the absence of diabetes, TGF-P can reproduce the deleterious effects of diabetic metabolic features on kidney cells. For example, high glucose causes mesangial cell (MC) hypertrophy (23,24) and stimulates collagen I and IV expression (14). In normal glucose media, exoge-nously added TGF-P1 also promotes MC hypertrophy and ECM production (14,23). For interstitial fibroblasts in culture, high glucose caused cellular proliferation and stimulated collagen I synthesis (25). Likewise, exogenous TGF-P1 was mitogenic for the interstitial fibroblast and TGF-P1 increased type-I collagen expression (25). Finally, experiments on cultured proximal tubular cells show that high glucose and TGF-P1 share similar actions (inhibition of proliferation, induction of cellular hyerp-trophy, and stimulation of ECM production) (15).

Perhaps the most important part of the modified Koch's postulates is that therapy targeted against the causative agent should ameliorate or cure the disease. In the case of DN, blocking the effects of TGF-P should prevent diabetes from causing renal pathology and dysfunction. Inhibition of the TGF-P system can be achieved with a PAN-selective, neutralizing anti-TGF-P antibody (26). Treating renal cells with this antibody, effectively prevented high glucose and other mediators of diabetes from inducing cellular hypertrophy and increasing matrix protein production, proving that these pathobiological effects are mediated by the cellular TGF-P system (14,23,27,28). Even more striking, the systemic treatment of diabetic animals with injected anti-TGF-P antibody prevented many of the structural and functional defects of DN, even though hyperglycemia was left untreated (6,8). In fact, neutralizing the TGF-P system ameliorated renal hypertrophy, normalized the overexpression of collagen IV and fibronectin, prevented the mesangial matrix expansion, and preserved renal function (8). These findings constitute the strongest evidence that the harmful effects of diabetes on the kidney are largely mediated by heightened activity of the intrarenal TGF-P system.

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