Abstract 133: Role of Vascular and Myeloid Mineralocorticoid Receptor in Renal Ischemia/reperfusion

Introduction: Renal ischemia/reperfusion (IR) is a major cause of acute kidney injury. It is associated with cardiac alterations and chronic kidney disease (CKD) development. We previously showed that mineralocorticoid receptor (MR) antagonism prevents the acute and chronic consequences of renal IR (Barrera-Chimal, Kidney Int, 2013 and JASN, 2015). However, whether the benefit of the MR antagonists is due to the blockade of the MR expressed in the vessels is unclear. Objective: To study the specific contribution of endothelial and smooth muscle cells MR in acute and chronic consequences of renal IR. Methods: To evaluate 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 inducible Cre recombinase under the VEcadh promoter. To allow MR inactivation in vascular smooth muscle cells (MR SMCKO mice), MR fl/fl mice were crossed with mice expressing the inducible Cre recombinase under the SMA promoter. In these mice, sham surgery or bilateral renal IR for 20 min was performed in MR fl/fl and KO mice and the animals were studied at short term (24 h) and long term (30 days) after reperfusion. 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 umol/L in IR), tubular injury and increased mRNA levels of kim-1 (400-fold) and NGAL (220-fold). The MR endoKO mice displayed similar alterations induced by IR as MR fl/fl mice. In contrast, after 24 h of renal IR, the MR SMCKO mice presented normal renal function (plasma creatinine was 9.6±0.7 and 14.0±1.9 umol/L in sham and IR, respectively), absence of histological alterations and reduced kim-1 and NGAL levels. After 30 days, the MR fl/fl mice developed CKD characterized by renal dysfunction (plasma creatinine from 10.5±0.1in sham to 15±0.8 umol/L in IR), tubule-interstitial fibrosis and increased mRNA levels of fibronectin and Galectin-3 (2-fold). The MR SMCKO mice developed similar alterations. Conclusion: We provide evidence that the deficiency of MR in the SMC protects against the development of acute kidney lesions induced by IR, however MR deficiency in SMC did not impact the appearance of CKD induced by IR.