TUDCA Attenuates High Salt‐Induced Renal Injury in ET B Deficient sl/sl Rats

Abstract

Endothelin (ET-1) mediates sodium excretion via the ETB receptor pathway, however the ET-1/ETA receptor pathway plays a role in salt-dependent hypertension. The mechanisms by which ET-1 leads to high salt-induced renal injury are unclear. Reports have associated endoplasmic reticulum (ER) stress with renal injury, thus we hypothesized that the loss of functional ETB receptors increases high salt-induced renal injury via activation of ER stress. ETB deficient (sl/sl) rats and transgenic controls were placed on normal (1% NaCl,NSD) or high salt (8%, HSD) diet for three weeks (n=5-7/group) with daily i.p. injections of saline or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 400 mg/kg/day). Histological injury assessments, urinary injury biomarkers, renal immune cell infiltration, renal apoptosis by TUNEL staining, and renal ER stress gene expression by qRT-PCR were studied. In sl/sl rats, HSD slightly increased glomerulosclerosis and significantly increased urinary markers of renal injury (KIM-1: NSD 14.2±3.4 to HSD 104.1±20.6 pg/day; NGAL: NSD 43.6±17.6 to HSD 215.6±27.7 pg/day, p<0.001) with no difference in control rats. TUDCA significantly decreased renal tubular damage in sl/sl rats (KIM-1: 55.7±13.8 pg/day; NGAL: 114.2±18.0 pg/day, p<0.05 vs. HSD alone). Renal ER stress markers, immune cell infiltration, and apoptosis were not different amongst groups. Thus, our data suggest that HSD contributes to renal tubular injury via cellular stress pathways and ETB receptor activation is reno-protective. Further investigation in the HSD-induced renal tubular stress pathways is warranted. Supported by NIH T32 DK007545 to CDM and P01 HL95499 to DMP and JSP.