Abstract 10422: Sesn2 Mediates Metformin Rescued Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome

Abstract

Introduction: Cardiorenal syndrome (CRS) consists of disorders of the kidneys and heart, whereby dysfunction of one organ may induce dysfunction of the other. Acute kidney injury (AKI) leads to a reduction in blood flow and energy supply to the heart. AMP-activated protein kinase (AMPK) as an energy sensor regulates energy metabolism via interacting with a scaffold protein Sesn2. The anti-diabetes drug metformin is an AMPK agonist, and it has been reported to regulate substrate metabolism under physiological and pathological conditions. But the beneficial role of metformin in CRS remains unknown. Hypothesis: Age-related impaired AMPK signaling contributes to cardiac intolerance to AKI-induced insults in the elderly. Metformin treatment ameliorates CRS through triggering Sens2/AMPK activation. Methods: Young (3-5 months) and aged (21-23 months) C57BL/6J wild type (WT), cardiomyocyte specific knock out (cSesn2 -/- ) and littermates (Sesn2 f/f ) C57BL/6J mice were subjected to AKI with a laparotomy and the renal artery and vein were clamped for 15 min followed by 72 hr of reperfusion (IRI). Seahorse XF Analyzer for mitochondrial respirational functions. Results: The higher levels of serum creatinine were observed after IRI-induced AKI in the aged versus young WT and cSens2 -/- versus Sesn2 f/f mice. Interestingly, administration of metformin can significantly reduce serum creatinine levels by IRI-induced AKI in young/aged WT and Sesn2 f/f but not cSesn2 -/- mice. Renal histological analysis showed higher incidence of tubular necrosis in the aged versus young AKI mice, the tubular necrosis was significantly reduced in the metformin treated young and aged AKI mice. Echocardiography data showed that AKI caused cardiac systolic dysfunctions in all experimental groups, while metformin treatment improved cardiac functions of young/aged WT and Sesn2 f/f but not cSesn2 -/- mice. Moreover, metformin treatment triggered AMPK activation and improved mitochondrial respiration rate and ATP production of cardiomyocytes from young/aged WT and Sesn2 f/f but not cSesn2 -/- hearts. Conclusions: Aging augments cardiac vulnerability to IRI-induced AKI. Metformin can rescue cardiac dysfunctions and renal injury caused by AKI through Sesn2/AMPK signaling pathway.