Background: Cardiorenal-syndrome is associated with high morbidity and mortality rates. This study tries to clarify the cardio-protective effects of carvedilol in 5/6 nephrectomized rats. Methods: The current study involved five groups of rats: sham, 5/6 nephrectomy, carvedilol (20mg/kg/day, i.p), amlexanox (25mg/kg/day, i.p), and carvedilol + amlexanox groups. Rats were subjected to 5/6 nephrectomy. Just after surgery, drugs were given for 10 weeks. At the end of study, kidney functions, blood pressure, and markers of cardiomyocyte apoptosis and heart failure were measured. Also, cardiac β1-adrenergic receptor signaling was measured. Results: 5/6 nephrectomy caused renal impairment, elevated both systolic and diastolic blood pressure and apoptosis with downregulation of cardiac β-arrestin2 down-stream proteins. On the contrary, carvedilol significantly reduced renal and cardiac deteriorations in 5/6 nephrectomized rats. Moreover, injection of amlexanox prior to carvedilol significantly reduced carvedilol-cardioprotective-effects. Conclusion: Carvedilol-induced cardiac protection in 5/6 nephrectomized rats is highly correlated with upregulation of cardiac G-protein coupled receptor kinase 5/β-arrestin2 pathway. Keywords: Carvedilol - β-arrestin2 - cardiorenal syndrome – amlexanox - G-protein coupled receptor kinase 5(GRK5)