UCP2 attenuates apoptosis of tubular epithelial cells in renal ischemia-reperfusion injury.

Uncoupling protein-2 (UCP2) plays critical roles in energy metabolism and cell survival. Previous investigations showed that UCP2 regulated the production of extracellular matrix and renal fibrosis. However, little is known about UCP2 in acute kidney injury (AKI). Here, we used Ucp2 knockout mice to investigate the role of UCP2 in an AKI model generated by renal ischemia-reperfusion (I/R) injury. The Ucp2 global knockout mice were born and grew normally without kidney histological abnormality or renal dysfunction. Compared with littermates, deletion of Ucp2 exacerbated I/R-induced AKI whereas increase of UCP2 by conjugated linoleic acid (CLA) attenuated I/R injury. Tubular cell apoptosis and autophagy were induced by I/R. After injury, more tubular cell apoptosis and less autophagy were identified in the kidneys of knockout mice compared with their littermates, and less apoptosis and more autophagy were observed in mice fed with CLA. In vitro rotenone, an inhibitor of electron transport chain complex I, was applied to induce energy depletion in cultured tubular epithelial cells. As expected, rotenone-recovery (R/R) treatment induced tubular cell apoptosis and autophagy. UCP2 plasmid transfection reduced cell apoptosis and facilitated autophagy after R/R treatment, whereas UCP2 small interfering RNA (siRNA) transfection sensitized cell apoptosis but reduced autophagy induced by R/R treatment. Interference of autophagy by treatment with autophagy inhibitor 3-methyladenine or autophagy initiation protein Beclin-1 siRNA transfection resulted in tubular cell apoptosis. Thus UCP2 attenuates I/R-induced AKI, probably by reducing cell apoptosis through protection of autophagy.