Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-,6 plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease /protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-fl. Ang 6 blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-ft and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of 6 expression. This mechanism may well contribute to glomerulosclerosis in vivo. (J. Clin. Invest. 1994. 93:2431-2437

The central pathological feature of human kidney disease that leads to kidney failure is the accumulation of extracellular matrix in glomeruli. Overexpression of transforming growth factor-beta (TGF-beta) underlies the accumulation of pathological matrix in experimental glomerulonephritis. Administration of an antibody raised against TGF-beta to glomerulonephritic rats suppresses glomerular matrix production and prevents matrix accumulation in the injured glomeruli. One of the matrix components induced by TGF-beta, the proteoglycan decorin, can bind TGF-beta and neutralize its biological activity, so decorin may be a natural regulator of TGF-beta (refs 3, 4). We tested whether decorin could antagonize the action of TGF-beta in vivo using the experimental glomerulonephritis model. We report here that administration of decorin inhibits the increased production of extracellular matrix and attenuates manifestations of disease, confirming our hypothesis. On the basis of our results, decorin may eventually prove to be clinically useful in diseases associated with overproduction of TGF-beta.

Diabetes is now the most common cause of progressive kidney failure leading to dialysis or transplantation. The central pathological feature of diabetic nephropathy is accumulation of extracellular matrix within the glomeruli. The factors in the diabetic milieu responsible for extracellular matrix accumulation are not understood. Here we report that in glomeruli of rats made diabetic there is a slow, progressive increase in the expression of transforming growth factor 1B (TGF-3) mRNA and TGF-,3 protein. A key action of TGF-,B is induction of extraceliular matrix production, and specific matrix proteins known to be induced by TGF-(3 were increased in diabetic rat glomeruli. These proteins include an alternatively spliced form of fibronectin, tenascin, and the proteoglycan biglycan. TGF-f8 has not previously been implicated in the matrix accumulation that occurs in the diabetic kidney. Glomeruli from humans with diabetic nephropathy also showed a striking increase in immunoreactive TGF-,B protein and deposition of the special form of fibronectin, whereas glomeruli from normal subjects or from individuals with other glomerular diseases (where extracellular matrix accumulation is not a feature) were negative or barely positive. These results implicate TGF-13 in the pathogenesis of diabetic nephropathy.Development of kidney disease is one of the most frequent and serious complications of diabetes and eventually occurs in patients despite treatment with insulin (1, 2). The dominant histological feature of diabetic nephropathy is the expansion of extracellular matrix in the mesangial areas of the glomeruli with resulting glomerulosclerosis and obliteration of the capillary surface area for filtration (3,4). Expansion of the mesangial matrix correlates strongly with the clinical onset of proteinuria, hypertension, and kidney failure (3, 4). Diabetes is considered a hormonal disorder, and organ complications such as kidney disease are usually attributed to metabolic consequences of abnormal glucose regulation such as elevated blood and tissue levels of glycosylated proteins (5) and/or hemodynamic changes within the kidney (6). However, whether this hypothesis is correct is unclear, and little is known about the molecular events underlying the matrix accumulation. This report presents evidence for the idea that diabetes can lead to elevated transforming growth factor ,B (TGF-f) expression and that this cytokine may be one cause of matrix deposition in the diabetic kidney.Three isoforms of B,81,82, are expressed in mammals and to date show similar properties in vitro (7). The role of TGF-,3 in regulating repair and regeneration following tissue injury is well documented (8). Platelets contain high concentrations of TGF-/3 and upon degranulation at a site of injury release TGF-P into the surrounding tissue (9). TGF-P then initiates a sequence of events that promotes healing including (i) chemoattraction of monocytes, neutrophils, and fibroblasts (10, 11); (ii) autoinduction ofTGF-f3 production and stimulation of ...

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Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.