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Protein kinase C- modulates mitochondrial function and active Na⁺ transport after oxidant injury in renal cells

Grayna Nowak, Diana Bakajsova, and Ginger L. Clifton

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Submitted 1 August 2003 ; accepted in final form 14 October 2003

The aim of this study was to determine whether protein kinase C- (PKC-) is involved in the repair of mitochondrial function and/or active Na⁺ transport after oxidant injury in renal proximal tubular cells (RPTC). Sublethal injury was produced in primary cultures of RPTC using tert-butylhydroperoxide (TBHP), and the recovery of functions was examined. PKC- was activated three- to fivefold after injury. Active PKC- translocated to the mitochondria. Basal oxygen consumption (QO₂), uncoupled QO₂, and ATP production decreased 58, 60, and 41%, respectively, at 4 h and recovered by day 4 after injury. At 4 h, complex I-coupled respiration decreased 50% but complex II- and IV-coupled respirations were unchanged. Inhibition of PKC- translocation using a peptide selective inhibitor, PKC-V1-2, reduced decreases in basal and uncoupled QO₂ values and increased complex I-linked respiration in TBHP-injured RPTC at 4 h of recovery. Furthermore, PKC-V1-2 prevented decreases in ATP production in injured RPTC. Na⁺-K⁺-ATPase activity and ouabain-sensitive ⁸⁶Rb⁺ uptake were decreased by 60 and 53%, respectively, at 4 h of recovery. Inhibition of PKC- activation prevented a decline in Na⁺-K⁺-ATPase activity and reduced decreases in ouabain-sensitive ⁸⁶Rb⁺ uptake. We conclude that during early repair after oxidant injury in RPTC 1) PKC- is activated and translocated to mitochondria; 2) PKC- activation decreases mitochondrial respiration, electron transport rate, and ATP production by reducing complex I-linked respiration; and 3) PKC- mediates decreases in active Na⁺ transport and Na⁺-K⁺-ATPase activity. These data show that PKC- activation after oxidant injury in RPTC is involved in the decreases in mitochondrial function and active Na⁺ transport and that inhibition of PKC- activation promotes the repair of these functions.

renal proximal tubular cells; recovery of physiological functions; respiratory chain; adenosine 5'-triphosphate production; sodium-potassium adenosinetriphosphatase

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