IN-VIVO TARGETING OF INDUCIBLE NO SYNTHASE WITH OLIGODEOXYNUCLEOTIDESPROTECTS RAT-KIDNEY AGAINST ISCHEMIA

Gene products of all three distinct nitric oxide synthases are present in the mammalian kidney, This mosaic topography of nitric oxide synth ase (NOS) isoforms probably reflects distinct functional role played b y each enzyme. While nitric oxide (NO) is cytotoxic to isolated renal tubules, inhibition of NO production in vivo invariably results in the aggravation of renal dysfunction in various models of acute renal fai lure. We reasoned that the existing ambiguity on the role of nitric ox ide in acute renal failure is in part due to the lack of selective NOS inhibitors. Phosphorothioated derivatives of antisense oligodeoxynucl eotides targeting a conserved sequence within the open reading frame o f the cDNA encoding the inducible NOS (iNOS) were designed to produce a selective knock-down of this enzyme, In vivo use of these antisense constructs attenuated acute rend failure in rats subjected to renal is chemia. This effect was due, at least in part, to the rescue of tubula r epithelium from lethal injury, Application of antisense constructs d id not affect endothelial NOS, as evidenced by a spared NO release aft er the infusion of bradykinin during in vivo monitoring with an NO-sel ective microelectrode. In conclusion, the data provide direct evidence for the cytotoxic effects of NO produced via iNOS in the course of is chemic acute renal failure, and offer a novel method to selectively pr event the induction of this enzyme. (J. Clin. Invest. 1996. 97:2377-23 83.)