Sirt1 Regulates The Mechanism Of Action Of Endoplasmic Reticulum Stress In The Pathophysiology Of Cardio-renal Syndrome

Objective: The aim of this study is about the role of Sirt1 on heart and renal function of Cardiorenal syndrome(CRS) which induced by subtotal nephrectomy and ligation LAD and the possible mechanism of Endoplasmic reticulum stress(ERS) in this model.Contents: We focus on the following issues in this study:(1) the effect of pure kidney lesions induced by subtotal nephrectomy(STNx) on heart structure and function.(2) The change of cardiac remodeling and pathophysiology post myocardial infarction with subtotal nephrectomy comparing with the normal kidney.(3) The cardiac remodeling and heart function will be aggravated or not by Cardiac-specific Sirt1 knockout(Sirt1 CKO).(4) The protective effect on cardiac remodeling post myocardial infarction with kidney disease or not post Cardiac-specific Sirt1 overexpression.Methods: Subtotal nephrectomy(STNx) plus LAD ligation was be used on C57BL/6 mouse to get Cardiorenal syndrome(CRS) animal model. Cardiac-specific Sirt1 knockout(Sirt1 CKO) and Cardiac-specific Sirt1 overexpression(Tg Sirt1) by injecting into the myocardium with Sirt1 lentivirus were performed in the following research to observe the effect of Sirt1 on the cardiorenal syndrome.Protocol 1:all of the mice were divided into:(1) group control:WT Sham STNx + Sham MI,(2) group WT MI: WT Sham STNx + MI,(3) group WT STNx + MI. Protocol 2:all of the mice were divided into:(1) Cre+/-Sirt1+/+ Sham STNx + Sham MI,(2) Cre+/-Sirt1+/+ Sham STNx + MI,(3) Cre+/-Sirt1+/+ STNx + MI,(4) Sirt1 CKO Sham STNx + Sham MI,(5) Sirt1 CKO Sham STNx + MI,(6) Sirt1 CKO STNx + MI.Protocol 3:(1) NTg Sirt1 Sham STNx + Sham MI,(2) NTg Sirt1 Sham STNx + MI,(3) NTg Sirt1 STNx + MI,(4) Tg Sirt1 Sham STNx + Sham MI,(5) Tg Sirt1 Sham STNx + MI,(6) Tg Sirt1 STNx + MI.All of the experimental mice were evaluated the cardiac and kidney function level pre and post operation 8 weeks. The BUN,Scr, BNP of serum and UACR of urine were tested by ELISA. The related protein of ERS in heart and kidney tissues’ detection were performed by western blot to find the physiopathologic mechanism of the effect of Sirt1 on cardiorenal syndrome. Results: After subtotal nephrectomy, glomerulus were getting swell and leaflet changes with the increased cell mounts and size, mesangial hyperplasia and the injury of the podocytes. Mild increasment of the serum and remarkable increasment of the UACR with deterioration of the kidney function while with the stable heart function. The cardiac remodeling and deterioration of the heart function post LAD ligation 4 weeks, enlargement of the heart chamber with the decline of the EF values and the increasing of the BNP level. No effect on the kidney function by pure LAD ligation was observed in our study. Comparing with the normal kidney groups, deterioration of cardiac remodeling and heart function were observed in the combined STNx and MI group. At the same time, the deterioration of the kidney function was happened in the combined STNx and MI group. Cardiac specific Sirt1 knock out deteriorated the effect of the STNx on the cardiac remodeling and heart function post MI, while cardiac specific Sirt1 overexpression could alleviate this effect. We found that the CHOP, GRP78 level of the heart tissue and the GRP78, Bax and p53 level of kidney tissue in Sirt1 CKO STNx + MI group were much higher than the control group. While the reverse results were presented in the Tg Sirt1 STNx + MI group comparing to the CKO group.Conclusions: Cardiac specific interpose of Sirt1 has effect on the heart and kidney structure and function in cardiorenal syndrome and the possible mechanism is related to the ERS.