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

Abstract

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 knockout mice to investigate the role of UCP2 in an AKI model generated by renal ischemia-reperfusion (I/R) injury. The global knockout mice were born and grew normally without kidney histological abnormality or renal dysfunction. Compared with littermates, deletion of 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.

UCP2‐dependent improvement of mitochondrial dynamics protects against acute kidney injury

“…UCP2 expression increased about three‐fold in renal tissue of LV‐ Ucp2 (Figure A) and CLA‐fed (see supplementary material, Figure A) mice compared with control mice. Immunostaining showed that UCP2 was expressed mainly in tubular epithelial cells, as previously reported and the tubular expression of UCP2 was markedly increased after lentivirus‐mediated gene transfection (Figure B). In AKI mice, both LV‐ Ucp2 and CLA‐fed restored renal function, evaluated as by BUN and Scr (Figure C and see supplementary material, Figure B) and ameliorated tubular injury in terms of reduction of tubular cell degeneration and necrosis (Figure D and see supplementary material, Figure C).…”

“…The protective role of autophagy was further confirmed in autophagy‐deficient mice . Currently, the protective role of UCP2 on I/R‐induced AKI by promoting autophagy and protecting renal tubule cells from apoptosis was established by the tests of UCP2‐deficient mouse models . In renal pathophysiology, the information about mitochondrial priming for mitophagy is scarce.…”

SB‐216763, a GSK‐3β inhibitor, protects against aldosterone‐induced cardiac, and renal injury by activating autophagy

“…A 3-MA is usually used to inhibit and study the mechanism of autophagy. 44 As shown in Figures 6A and 6B, the level of perivascular fibrosis and tubulointerstitial injury score increases after Aldo treatment, whereas SB-216763 can reverse the alteration. More important, pharmacological inhibition of autophagy by 3-MA markedly inhibits the role of SB-216763 in suppressing perivascular fibrosis and tubulointerstitial injury.…”

Mitochondrial energetics in the kidney

“…An increase in ROS formation in the mitochondria activates UCP2, dissipating the proton motive force as heat and, as a result, reducing ROS production 36,37 . As ROS production contributes to mitochondrial dysfunction in AKI and diabetic nephropathy, UCP2 has been explored in the kidney and in these disease states 38 . Studies investigating the role of UCP2 polymorphisms in the kidney that exacerbate disease in patients with diabetic nephro pathy reveal that UCP2 is a potential target for treatment 39 .…”

“…Studies investigating the role of UCP2 polymorphisms in the kidney that exacerbate disease in patients with diabetic nephro pathy reveal that UCP2 is a potential target for treatment 39 . Lack of UCP2 has also been shown to worsen tubular injury after induction of experimental AKI in mice 38 . These studies show the importance of UCP2 in the kidney as well as its role in attenuating excessive ROS production.…”