Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity.
BACKGROUND
L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase producing NO, and the NO synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME), have both been shown to modify acute cyclosporine (CsA)-induced intrarenal vasoconstriction. However, the mechanism of chronic CsA nephrotoxicity characterized by progressive tubulointerstitial fibrosis (TIF) remains unclear. Thus, we examined the pathogenetic role of NO in a rat model of chronic CsA nephropathy.


METHODS
Rats were given vehicle, CsA (7.5 mg/kg), CsA + L-Arg (1.7 g/kg), CsA + D-arginine (1.7 g/kg), and CsA + L-NAME (3.5 mg/kg) for 28 days on a low-salt diet. NO production, glomerular filtration rate (GFR), blood and urine chemistry, and histology were assessed.


RESULTS
L-Arg treatment significantly enhanced NO biosynthesis and protected animals from impaired GFR and development of TIF induced by CsA, whereas D-arginine did not. In contrast, L-NAME strikingly reduced urinary NO and worsened both GFR and TIF compared to the CsA alone group, whereas L-NAME did not change renal function and histology in the vehicle group.


CONCLUSIONS
Chronic CsA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement, suggesting that NO has an important role in the mechanism of chronic CsA nephropathy.
Andoh
T F
TF
Department of Medicine, Oregon Health Sciences University, Portland 97201, USA.
Gardner
M P
MP
Bennett
W M
WM
D000818:Animals; D001120:Arginine / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000097:blood / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000097:blood / Q000633:toxicity*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000139:chemically induced / Q000517:prevention & control
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester