0227 : Mineralocorticoid receptor deficiency in smooth muscle cells protects against renal injury induced by ischemia/reperfusion

Introduction Renal ischemia/reperfusion (IR) is an important cause of acute kidney injury (AKI). AKI has been linked with progression to chronic kidney disease and development of cardiac alterations. Previous studies from our laboratory have shown that mineralocorticoid receptor (MR) antagonism with spironolactone prevents tubular injury and renal dysfunction induced by IR. The protection mechanisms remain unclear and whether the blockade of vascular MR is responsible for the protection conferred by MR antagonists in IR remains unexplored. Objective To evaluate the specific contribution of vascular MR in the development of the kidney injury induced by IR. Methods To investigate the contribution of vascular MR we generated two knockout (KO) mouse models. To allow MR inactivation in endothelial cells (MR endoKO mice), floxed MR mice (MR fl/fl ) were crossed with mice expressing the Cre recombinase under the Tie2cre promoter. To allow MR inactivation in smooth muscle cells (MR SMCKO mice), MRfl/fl mice were crossed with mice expressing the inducible Cre recombinase under the SMA promoter (MR SMCKO ). In these mice, sham surgery or bilateral renal IR for 20min was performed. The animals were studied 24 h after reperfusion. As markers of tubular injury, the mRNA levels of Kim-1 and NGAL were quantified. Results In MR fl/fl mice, IR induced renal dysfunction (plasma creatinine raised from 8.9±0.3 in sham to 33.8±4.8 μmol/L in IR), tubular injury and an increase in mRNA levels of Kim-1 (400-fold) and NGAL (200-fold). The MR endoKO mice displayed similar alterations induced by IR as MR fl/fl mice. In contrast, after renal IR, the MR SMCKO mice presented normal renal function (plasma creatinine was 9.6±0.7 and 14.0±1.9 μmol/L in sham and IR, respectively), absence of histological alterations and a significant reduction in the mRNA levels of Kim-1 and NGAL. We are now testing the effect of MR deficiency in smooth muscle cells in preventing the development of chronic alterations induced by IR. Conclusion We show that the deficiency of the MR expressed in smooth muscle cells protects against the renal injury induced by IR. Our data provides further evidence to support the use MR antagonists as a novel therapeutic approach to prevent acute and chronic consequences of renal IR.