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TOXICOLOGY

Protein Kinase C Mediates Repair of Mitochondrial and Transport Functions after Toxicant-Induced Injury in Renal Cells

Grayna Nowak

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Previously, we have shown that renal proximal tubular cells (RPTCs) recover physiological functions after injury induced by the oxidant tert-butylhydroperoxide (TBHP), but not by the nephrotoxic cysteine conjugate dichlorovinyl-L-cysteine (DCVC). This study examined the role of protein kinase C (PKC) in the repair of RPTC functions after sublethal injury produced by these toxicants. Total PKC activity decreased 65 and 86% after TBHP and DCVC exposures, respectively, and recovered in TBHP-injured but not in DCVC-injured RPTCs. Mitochondrial function, active Na⁺ transport, and Na⁺-dependent glucose uptake decreased after toxicant exposure and recovered in TBHP- but not in DCVC-injured RPTCs. PKC inhibition decreased the repair of RPTC functions after TBHP injury. PKC activation promoted recovery of mitochondrial function and active Na⁺ transport in TBHP- and DCVC-injured RPTCs but had no effect on recovery of Na⁺-dependent glucose uptake. We conclude that in RPTCs, 1) total PKC activity decreases after TBHP and DCVC injury and recovers after TBHP but not after DCVC exposure, 2) recovery of PKC activity precedes the return of physiological functions after oxidant injury, 3) PKC inhibition decreases recovery of physiological functions, and 4) PKC activation promotes recovery of mitochondrial function and active Na⁺ transport but not Na⁺-dependent glucose uptake. These results suggest that the repair of renal functions is mediated through PKC-dependent mechanisms and that cysteine conjugates may inhibit renal repair, in part, through inhibition of PKC signaling.

Address correspondence to: Dr. Grayna Nowak, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham St., MS 522-3, Little Rock, AR 72205. E-mail: gnowak{at}uams.edu

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