0278 : Mineralocorticoid receptor antagonism with BR-4628 protects against renal injury induced by ischemia/reperfusion

Introduction The main cause of acute kidney injury (AKI) is ischemia/ reperfusion (IR). AKI has been associated with chronic kidney disease progression and cardiac alterations. Previous studies showed that in a rat model of kidney IR, mineralocorticoid receptor (MR) antagonism with spironolactone prevents tubular injury and renal dysfunction. Despite their benefits in renal diseases, the current MR antagonists have strong limitations like hyperkalemia, thus motivating the search of novel antagonists with safer profile. Objective Test the efficacy of the non-steroidal MR antagonist BR-4628 against renal injury induced by IR. Methods Twenty male wistar rats were divided in 4 groups: sham-operated (S), bilateral renal ischemia (IR) for 25min, treated with BR-4628 (10mg/kg) either 3 days before IR (B10-pre) or 3 hours after IR (B10-post). All groups were studied 24h after reperfusion. Blood sample was taken for creatinine and urea quantification. The right kidney was processed for molecular studies and the left for histopathological analysis. Results Rats with IR developed renal injury characterized by renal dysfunction, increase in tubular injury markers (Hsp72 and Kim-1), oxidized proteins and pro-inflammatory cytokines. These alterations were absent in the B10-pre and B10-post IR groups. IR induced an increased expression of the M1 macrophage markers iNOS, CCL3, TNF-alpha and MCP-1 (inflammatory phenotype) that was fully prevented with the BR-4628 pre-treatment. Furthermore we observed that in the B10-pre and B10-post groups there was a greater expression of M2 macrophage markers; IL4r, FIZZ1 and Igfr2 (wound healing phenotype), as compared to the non-treated IR group. Conclusion We show for the first time that the non-steroidal BR-4628 MR antagonist is effective to prevent or treat renal injury induced by IR possibly through a mechanism involving macrophage polarization towards the wound healing phenotype.