We recently discovered that a low protein diet, an established and beneficial treatment in progressive renal diseases, significantly ameliorated the course of experimental glomerulonephritis (ATS-GN) in the rat. In an additional study, we found that a low L-arginine diet produced exactly the same result as a low protein diet. Both diets also decreased Transforming Growth Factor-B (TGF-beta) expression which is a cytokine capable of inducing flbrotic changes in chronic diseases. We also found that L-NMMA, an inhibitor of nitric oxide (NO) synthesis, prevented glomerular injury in this model. The amino acid I--arginine is metabolized by 2 different enzymes: a) by nitric oxide synthase to NO and L-citrulline; and b) by arginase to L-ornithine and urea. Whereas NO is a potentially cytotoxic molecule in tissue injury, I--ornithine is a substrate for polyamine and L-proline synthesis. Polyamines are required for growth and proliferation, L-proline is a substrate for collagen synthesis, an important pathological component of fibrotic tissues. We now also have evidence that L-arginine or products of L-arginine metabolism are potential regulators of TGF-B expression in the course of chronic flbrotic disease. Thus, we have hypothesized that activated L-arginine metabolism may be a key contributor to tissue injury, repair processes and fibrosis and the low L-arginine content of low protein diets may act by ameliorating these effects. In ATS-GN, we have shown that L-arginine metabolism is activated in a sequential pattern: early activation of NO synthesis followed by increased arginase activity, polyamine and proline synthesis. However, this animal model represents an acute and self-limiting disease and can not be compared directly to progressive kidney diseases. Therefore, the proposed studies will investigate L-arginine metabolism in 3 chronic rat models that resemble the most common diseases leading to renal failure in humans: 1) diabetic nephropathy (streptozocin-induced); 2) chronic glomerulonephritis (ATS-GN with repeated ATS injection); and 3) hypertensive glomerulopathy (angiotensin-fl-induced). Molecular biology techniques, biochemical methods and histological examination of kidney tissues will be applied. The studies will provide understanding of the regulation of L-arginine metabolism in chronic progressive kidney diseases, evaluate the role of TGF-beta in this context and specifically focus on therapeutic approaches. These therapies would include dietary modulation of L-arginine intake and administration of antagonists of L-arginine metabolizing enzymes. The goal of these studies will be to develop new and effective treatments to prevent or reverse progressive injury and fibrosis in chronic kidney diseases and thereby slow their progression towards renal failure.
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