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Production and Actions of Superoxide in the Renal Medulla

A. Zou,Ningjun Li,A. Cowley

Published 2000 in HYPERTENSION

ABSTRACT

The present study characterized the biochemical pathways responsible for superoxide (O2−·) production in different regions of the rat kidney and determined the role of O2−· in the control of renal medullary blood flow (MBF) and renal function. By use of dihydroethidium/DNA fluorescence spectrometry with microtiter plates, the production of O2−·was monitored when tissue homogenate from different kidney regions was incubated with substrates for the major O2−·-producing enzymes, such as NADH/NADPH oxidase, xanthine oxidase, and mitochondrial respiratory chain enzymes. The production of O2−· via NADH oxidase was greater (P <0.05) in the renal cortex and outer medulla (OM) than in the papilla. The mitochondrial enzyme activity for O2−·production was higher (P <0.05) in the OM than in the cortex and papilla. Compared with NADH oxidase and mitochondrial enzymes, xanthine oxidase and NADPH oxidase produced much less O2−· in the kidney under this condition. Overall, the renal OM exhibited the greatest enzyme activities for O2−·production. In anesthetized rats, renal medullary interstitial infusion of a superoxide dismutase inhibitor, diethyldithiocarbamate, markedly decreased renal MBF and sodium excretion. Diethyldithiocarbamate (5 mg/kg per minute by renal medullary interstitial infusion [RI]) reduced the renal medullary laser-Doppler flow signal from 0.6±0.04 to 0.4±0.03 V, a reduction of 33%, and both urine flow and sodium excretion decreased by 49%. In contrast, a membrane-permeable superoxide dismutase mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL, 30 &mgr;mol/kg per minute RI) increased MBF and sodium excretion by 34% and 69%, respectively. These effects of TEMPOL on renal MBF and sodium excretion were not altered by pretreatment with NG-nitro-l-arginine methyl ester (10 &mgr;g/kg per minute RI). We conclude that (1) renal medullary O2−·is primarily produced in the renal OM; (2) both NADH oxidase and mitochondrial enzymes are responsible for the O2−· production in this kidney region; and (3) O2−· exerts a tonic regulatory action on renal MBF.

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