Protective effect of oral L-arginine supplementation on cyclosporine induced nephropathy in rats.
BACKGROUND
One of the major adverse effects of long term cyclosporine A (CyA) administration is chronic nephrotoxicity. Several studies have suggested that alterations of the L-arginine (L-Arg) nitric oxide (NO) pathway may be involved in the pathogenesis of CyA-induced kidney damage.


OBJECTIVE
We postulated that in vivo activation of L-Arg-NO pathway might have a beneficial effect on CyA-induced renal damage. Conditions of chronic NO enhancement was established with L-Arg supplementation and chronic NO blockade with N-nitro-L-Arg methyl ester (L-NAME). We tested the hypothesis that, if CyA administration alters intrarenal NO synthesis, then exogenous L-Arg supplementation could limit renal injury, on the contrary, L-NAME, a potent competitive inhibitor of NO synthesis, could enhance CyA nephrotoxicity. Harmful effect of NO blockade indirectly supports the beneficial effect of NO in a model of CyA nephrotoxicity.


METHODS
Rats were administered vehicle (VH), CyA (7.5 mg/kg/day), CyA + L-Arg (2g/kg/day), CyA + L-NAME (5 mg/100 ml/day), CyA + L-Arg + L-NAME, VH + L-Arg, VH + L-NAME and were sacrificed at the end of the experiment. Body weight, serum creatinine, blood urea nitrogen (BUN) and NO levels were determined. Tubular injury and interstitial fibrosis were evaluated semiquantitatively using scoring systems on paraffin sections stained with hematoxylin/eosin (H/E), Masson's trichromic and periodic acid-Schiff (PAS).


RESULTS
The CyA group developed marked renal injury, characterized by a significant increase in serum creatinine and BUN, and histopathological alterations including tubular dilatation, vacuolization, necrosis, interstitial cell infiltration and tubulointerstitial fibrosis. CyA reduced serum NO level. L-Arg treatment significantly enhanced NO biosynthesis and protected animals from CyA-induced kidney damage. In contrast L-NAME strikingly reduced serum NO level, and worsened biochemical and histopathological alterations.


CONCLUSIONS
Chronic CyA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement suggesting that L-Arg supplementation may be protective in CyA nephrotoxicity.
Kuruş
Meltem
M
Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey.
Eşrefoğlu
Mukaddes
M
Bay
Aysun
A
Oztürk
Feral
F
D000818:Animals; D001120:Arginine / Q000008:administration & dosage*; D001284:Atrophy; D016572:Cyclosporine / Q000009:adverse effects; D019587:Dietary Supplements; D005260:Female; D005919:Glomerular Filtration Rate; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester