Transforming growth factor beta contributes to progressive diabetic nephropathy.

R failure is a common and serious complication of longstanding diabetes mellitus. Diabetes is now the most common cause of end-stage renal failure requiring dialysis in the United States, accounting for almost 40% of all new dialysis patients (1). Moreover, the incidence of renal failure caused by diabetes, particularly type II diabetes, is rising dramatically worldwide (2). Compounding the tragedy of the explosive growth in the incidence renal failure caused by diabetes is the grim reality that the survival of patients with renal failure caused by diabetes is much worse than that of patients with renal failure resulting from other causes. In Germany, for example, Koch et al. (3) reported a 5-year survival of only 5% among patients with type II diabetes undergoing dialysis. Fortunately, progress is being made in our understanding of the pathogenesis of diabetic renal disease and in our ability to delay, or even prevent, this devastating complication. Two studies appearing in this issue of PNAS (4, 5) are illustrative of this progress. Diabetic nephropathy refers to a characteristic set of structural and functional kidney abnormalities that occur in patients with diabetes. Although best described in patients with type I diabetes (6), similar findings are now known to occur in the more common type II diabetic patient (7). Structural abnormalities include hypertrophy of the kidney, an increase in the thickness of glomerular basement membranes, accumulation of extracellular matrix components in the glomerulus (nodular and diffuse glomerulosclerosis), tubular atrophy, and interstitial fibrosis (6, 7). Functional alterations include an early increase in the glomerular filtration rate with intraglomerular hypertension, subsequent proteinuria, systemic hypertension, and eventual loss of renal function (8). Clinicopathologic studies of diabetic nephropathy have established that the extent of matrix accumulation in both the glomeruli and the interstitium correlate strongly with the degree of renal insufficiency and proteinuria (9). Accordingly, the factors responsible for the deposition and accumulation of extracellular matrix material within the kidney are of considerable interest. A host of mediators, such as hyperglycemia, glycosylated proteins, intracellular polyols, vasoactive hormones, systemic and glomerular hypertension, proteinuria, growth factors, and cytokines have been implicated in the pathogenesis of diabetic nephropathy (10, 11). Of these, the cytokine transforming growth factor (TGF-b) has emerged as having a key role in the development of renal hypertrophy and accumulation of extracellular matrix in diabetes (10, 12). TGF-b is known to have powerful fibrogenic actions resulting from both stimulation of matrix synthesis and inhibition of matrix degradation (12). In humans and animal models, TGF-b mRNA and protein levels are significantly increased in the glomeruli and tubulointerstitium in diabetes (13–17). Moreover, short-term administration of TGF-b neutralizing antibodies to rats with chemically induced diabetes prevented glomerular enlargement and suppressed the expression of genes encoding extracellular matrix components (18). The study reported by Ziyadeh et al. (4) in this issue of PNAS extends these observations and provides the strongest evidence to date for the causal role of TGF-b in the structural and functional abnormalities of diabetic nephropathy. Specifically, Ziyadeh et al. (4) examined the effects of long-term administration of a neutralizing TGF-b antibody on the renal function and renal histology of diabetic mice. These mice, the dbydb strain, lack the hypothalamic leptin receptor and develop obesity caused by overeating, insulin resistance, and hyperglycemia. In these respects, the dbldb mouse is a model of type II diabetes mellitus, which accounts for about 70–80% of all diabetic end-stage renal failure (1). Kidneys from untreated dbydb mice exhibited an increase in TGF-b mRNA expression in glomeruli and an increase in TGF-b receptor expression when compared with nondiabetic dbym littermates. Similarly, there was an increase in kidney type IV collagen a1 and fibronectin mRNA expression and histologic evidence of mesangial matrix expansion in the dbldb mice. Functional abnormalities of diabetic nephropathy included a 40% fall in the glomerular filtration rate and a large increase in urinary albumin excretion. Remarkably, treatment with the neutralizing antibody almost completely prevented the increase in collagen and fibronectin expression and the mesangial matrix expansion in the diabetic mice. These results are quite consistent with previous in vitro studies demonstrating the effects of TGF-b on production of extracellular matrix components (19, 20). The most significant finding, though, was that neutralization of TGF-b prevented the fall in glomerular filtration rate. Thus, these results provide clear evidence that TGF-b activity contributes to the development of diabetic glomerulosclerosis and, ultimately, to renal failure. A curious observation in this study was the failure of the TGF-b neutralizing antibody to reduce proteinuria in the diabetic mice. Proteinuria is an early manifestation of diabetic nephropathy and is a powerful predictor of subsequent renal dysfunction (21). Indeed, it has been suggested that proteinuria itself plays a pathogenic role in diabetic nephropathy and other renal diseases (22). That Ziyadeh et al. (4) were able to dissociate proteinuria from the development of glomerulosclerosis and renal insufficiency permits two conclusions. First, TGF-b is apparently not a key factor in the glomerular hemodynamic and permeability changes that result in proteinuria. Second, the deleterious effects of proteinuria on the progression of renal disease may themselves be mediated via TGF-b. The study by Lang et al. (5), also in this issue of PNAS, addresses the possible role of a serineythreonine kinase, hSGK, in the dysregulation of sodium transport in the diabetic kidney. hSGK, found in most tissues (23) is known to be up-regulated by TGF-b (24). Lang et al. (5) found that increasing the extracellular glucose concentration increased hSGK expression in cultured fibroblasts and endothelial cells. Moreover, the effect of glucose was mediated through a pathway involving