Urinary metabolomics analysis to reveal metabolic mechanism of guanxinning injection on heart failure with renal dysfunction

Consistently, the multiple heart-kidney interactions make pharmaceutical research for cardiorenal syndrome difficult and complex. Guanxinning Injection (GXN) has been reported to provide unique advantage for treating cardiac and renal diseases compared to typical monotherapies. However, the protection mechanism of GXN is largely unknown. This study explored the acting mechanism of GXN on heart failure with renal dysfunction from a metabolic perspective. Transverse aortic constriction (TAC) surgery was performed on C57/BL/6 mice to induce heart failure with renal dysfunction. Using telmisartan as a positive control, GXN treatment was applied during the 12th to 16th week after TAC. Cardiac function and structure were examined using M-mode echocardiography, and renal function was evaluated via representative biochemical parameters and hematoxylin-eosin staining. Moreover, untargeted metabolomic analyses of urine were conducted to screen for differential substances associated with the cardiorenal protection effect of GXN. As a result, GXN provided good cardioprotective effects on left ventricular ejection fraction elevation, fractional shortening, internal diastolic, and mass maintenance. GXN also reduced TAC-induced elevation of blood urea nitrogen, and serum Cystatin C and relieved kidney pathological damage. Metabolomic analyses identified 21 differential metabolites in the TAC model group. Ten metabolites involving the metabolic pathways of carnitine synthesis, valine, leucine and isoleucine degradation, and glutamate metabolism, taurine and hypotaurine metabolism, tryptophan metabolism, arginine and proline metabolism, and purine metabolism were restored by GXN. The main cardiorenal protection mechanism of GXN was found to be related to energy metabolism and oxidative stress. Taken together, this study provides the first evidence of the metabolic protection mechanism of GXN on heart failure with renal dysfunction for the first time and provides a research basis for the application of GXN in CRS-2 pharmaceuticals.