Abstract 293: Role Of G-protein Coupled Receptor Signaling In Cardio-renal Injury

Abstract

The kidneys play an important role in cardiovascular disease (CVD), where renal co-morbidities accompany CVD in a large proportion of patients thus complicating their treatment regimen. Moreover, the incidence of acute renal injury after cardiac surgery plays an important role in disease progression. Emerging data suggest the importance of understanding the mechanisms of cardio-renal injury and the development of novel therapies that can be safely used with cardiovascular and renal co-existing pathologies. Although the role of G-protein coupled receptors (GPCRs) in CVD has been broadly recognized, their role in renal injury remains poorly understood. We have found, in a chronic mouse model of heart failure, attenuated renal fibrosis and attenuated pathologic RAAS activation by the small molecule GPCR-Gβγ inhibitor “gallein”. To investigate the direct effects of GPCR-Gβγ inhibition on renal injury, we utilized an acute renal ischemia-reperfusion (RIR) mouse model. Gβγ inhibition by gallein pretreatment attenuated the histopathological profile of RIR, including attenuation of tubular hypertrophy, apoptosis, cast formation, and tissue Lipocalin2 expression. This was accompanied by attenuated inflammation, reflected by reduced CCL2 and ICAM1 gene expression and cellular infiltration, in addition to reduced Collagen III gene expression. These preliminary results suggest a promising protective role for Gβγ inhibition in renal injury and remodeling. Future mechanistic investigation of this possible protective effect will provide better understanding of the role of GPCR-Gβγ signaling in cardio-renal injury and remodeling and possible novel therapeutic targets.