RESUMO
Fibrosis is a common feature of chronic kidney disease; however, no clinical therapies effectively target the progression of fibrosis. Inhibition of fibronectin polymerization with the small peptide pUR4 attenuates fibrosis in the liver and heart. Here, we show that pUR4 decreases renal fibrosis and tissue remodeling using a clinically relevant model of kidney injury, unilateral ischemia-reperfusion. This work highlights the benefits of inhibiting matrix polymerization, alone or in conjunction with cell-based therapies, as a novel approach to diminish the maladaptive responses to ischemic kidney injury that lead to chronic renal failure.
Assuntos
Injúria Renal Aguda/prevenção & controle , Matriz Extracelular/efeitos dos fármacos , Fibronectinas/metabolismo , Rim/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Polimerização , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gßγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gßγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gßγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gßγ-GRK2 interactions. Further, we explore the potential of GPCR-Gßγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.