Involvement of Endoplasmic Reticulum Stress in Uremic Cardiomyopathy: Protective Effects of Tauroursodeoxycholic Acid.

BACKGROUND/AIMS Uremic cardiomyopathy (UCM) is a complication in chronic kidney disease. We investigated if endoplasmic reticulum stress (ERS) is involved in UCM, and determined the efficacy of tauroursodeoxycholic acid (TUDCA) in UCM prevention. METHODS Mice were divided randomly into three groups: sham (saline, i.p), 5/6 nephrectomized (Nx) (saline, i.p) and Nx+TUDCA (250 mg/kg/day, i.p.). Renal function was assessed by measuring serum creatinine, blood urea nitrogen and by periodic acid-Schiff reagent staining. Histologic examination of cardiac fibrosis and apoptosis was determined by Masson's trichrome and TUNEL assay. Cardiac function was evaluated by echocardiography. Fibrotic factors (transforming growth factor-β, fibronectin, collagen I/IV) were evaluated by real-time PCR. ERS-related proteins were measured by western blotting. RESULTS Impaired renal function and cardiac dysfunction were shown in 5/6 nephrectomy mice but were improved significantly by TUDCA. 5/6 nephrectomy mice exhibited marked cardiomyocyte apoptosis, cardiac fibrosis and elevated pro-fibrotic factors. ERS markers (GRP78, GRP94, P-PERK, P-eIF2a) and ERS-induced apoptosis pathways (activation of CHOP and caspase-12) were increased significantly in 5/6 nephrectomy mice, and TUDCA treatment blunted these changes. CONCLUSIONS ERS has a key role in UCM, and the cardioprotective role of TUDCA is related to inhibition of ERS-induced apoptosis by inhibition of CHOP and caspase-12 pathways.