ИСТИНА

INTRODUCTION AND AIMS: Ischemia and reperfusion (I/R) of kidney is one of the leading causes of the acute kidney injury (AKI). I/R leads to mitochondrial dysfunction and overproduction of reactive oxygen species. Oxidative stress could affect endothelial function and this may be explanation for deterioration of renal hemodynamics observed during AKI. The aim of this work to study the ability of mitochondria-targeted antioxidant SkQR1 to prevent endothelial dysfunction of kidney during I/R. METHODS: EaHy926 cells were exposed to 5 hrs of oxygen-glucose deprivation (OGD) to study the effect of I/R on endothelium in vitro. Cell viability was measured by MTT 24 hrs after OGD. I/R of left kidney was performed in male rats to study ischemic AKI in vivo. Renal pedicle of left kidney was clamped for 40 min and the right kidney was removed. The severity of renal failure was assessed by the serum levels of creatinine (SCr) and blood urea nitrogen (BUN) 48 hrs after I/R. Renal blood flow (RBF) was measured by high frequency ultrasound Doppler system. Accumulation of Evans Blue dye in kidney parenchyma 1 hrs after intravenous injection was used to assess permeability of renal vasculature. The morphology of endothelium of kidney cortex after I/R was studied by electron microscopy. RESULTS: OGD decreased viability of cells to 48%. I/R in vivo resulted in pronounced increase of SCr and BUN (4.2 and 5.7 times respectively vs control rats). Electron microscopy of kidney cortex fixed 10 min after I/R revealed alterations in morphology of mitochondria in endothelial cells. 30 min after IR RBF was 48% of preischemic values and renal artery resistance index (RI) was increased from 0.67 (preischemia) to 0.89. 48 hrs after I/R the amount of Evans Blue dye penetrated into kidney parenchyma increased from 0.82 to 1.06 ng/mg kidney weight (vs control rats) indicating augmentation of renal vascular permeability. Preincubation with SkQR1 (25nM) for 1 hrs increased viability of OGD-exposed EaHy926 cells to 64%. Treatment of rats with SkQR1 (100 nmol/kg i.p.) 3 hrs before and 1, 18, 30 and 42 hrs after I/R diminished SCr and BUN levels to 56% and 53% respectively (vs I/R rats) and attenuated endothelial dysfunction. 30 min after I/R RBF in SkQR1-treated rats increased to 67% of preischemic values and RI decreased to 0.64. Evans Blue penetration into kidney parenchyma decreased to 0.82 ng/mg kidney weight. Co-treatment of animals with SkQR1 and Nω-Nitro-L-arginine (1 mg/kg i.v. 15 min before I/R) abolished beneficial effect of SkQR1 both on renal function and renal hemodynamics. CONCLUSIONS: Mitochondria-targeted antioxidant SkQR1 attenuates endothelial dysfunction and renal failure after ischemic AKI. Supported by RFBR grants: 16-34-01314, 14-04-00542 and 14-04-00300.