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1 Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
* To whom correspondence should be addressed. E-mail: nli{at}vcu.edu.
The present study was designed to test the hypothesis that the production of superoxide (O2.-) by NAD(P)H oxidase is coupled to tubular metabolic activity through ionic activation mediated by H+ movement across cell membrane. Using dual fluorescent microscopic imaging analysis, intracellular O2.- levels and pH (pHi) in renal medullary thick ascending limb of Henle (TALH) cells were simultaneously measured. It was found that intracellular O2.- levels in these cells were increased in parallel to the elevation of pHi by outflow of H+ induced via NH4Cl loading followed by rapid removal. This increase in intracellular O2.- levels was substantially blocked by an inhibitor of Na+/H+ exchanger, methylisobutyl-amiloride (MIA, 100 µM), a chemical SOD mimetic, Tiron (1 mM) or an inhibitor of NAD(P)H oxidase, diphenylene iodonium (DPI, 100 µM). In additional groups of TALHs, a proton ionophore, carbonylcyanide m-chlorophenylhydrazone (CCCP, 10 µM) was used to produce H+ conductance, leading to H+ flux across cell membrane depending on extracellular pH. The efflux of H+ increased both pHi and intracellular O2.- levels, but the influx of H+ did not increase intracellular O2.- levels. The H+ efflux-induced increase in intracellular O2.- levels was completely blocked by DPI and another NAD(P)H oxidase inhibitor, apocynin (100 µM). In in invo experiments, renal medullary infusion of MIA (100 µM) was found to significantly decrease the concentrations of H2O2 in the renal medullary interstitium. These results suggest that it is the outward movements of H+ ions that activates NAD(P)H oxidase to produce O2.- in TALH cells. This H+ outflow-associated activation of NAD(P)H oxidase importantly contributes to tissue levels of reactive oxygen species (ROS) in the renal medulla.
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