Abstract
The past decade has witnessed an explosive growth of literature related to the role of nitric oxide (NO) in renal physiology and pathophysiology. Alterations of renal NO generation have been incriminated in various renal disorders. Excessive production of NO by NOS II in infiltrating immune cells and mesangial cells was described in acute glomerulonephritides and inhibition of NOS II resulted in protection from such renal injury [1]. Sustained high output generation of NOS II mediated NO, often accompanied by consequent suppression of NOS III derived NO is characteristic of endothelial dysfunction in ischemic acute renal injury [2]. Selective NOS II inhibition with L-N6-(1-iminoethyl) lysine or NOS II knockout rats demonstrated protection in acute ischemic renal failure models [3]. Diabetic nephropathy is characterized initially by increased renal NO production, primarily derived from NOS III, which is believed to account for glomerular hyperfiltration and microalbuminuria. On the other hand advanced diabetic nephropathy as well as most forms of chronic renal injury are associated with incremental renal NO deficiency, a consequence of NOS inhibition (mainly NOS II and NOS III) by hyperglycemia [4], and several other mediators [5]. In animal models of diabetic nephropathy, inhibition of NOS II and III has been shown to accelerate renal structural damage and functional impairment. Dietary supplementation of L-arginine, a precursor of NO, in diabetic rats resulted in reduction in proteinuria and renal injury [6]. Metabolic acidosis, a common consequence of renal failure may contribute to decreased intrarenal NO synthesis, since reduced extracellular pH impairs oxidation of nicotinamide dinucleotide phosphate (NADPH), an important post-translational mechanism in NOS II activation [7]. Urea in general leads to inhibition several enzyme systems in the body including NOS enzymes which could account for macrophage dysfunction in uremia [8]. In summary, inhibition of NOS has variable effects of renal structure and function, being renoprotective in acute glomerular and ischemic renal injury while accelerating structural damage, proteinuria, and renal failure in most forms of chronic renal failure [9], particularly in diabetes. These observations are not only crucial in understanding the pathophysiology but also provide potentially novel therapeutic targets in various renal disorders.
Keywords: Nitric oxide, nephropathy, nitric oxide synthase, endothelial dysfunction, diabetes, acute kidney injury
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