The molecular mechanisms by which the vasoactive peptide endothelin-1 (ET-1) leads to high salt-induced renal damage remain uncertain. These studies were designed to determine if the ET system induces renal damage by increasing renal cellular stress. ET B deficient (ET B def) and transgenic (TG) control rats were placed on normal (NSD, 1% NaCl) or high salt (HSD, 8% NaCl) diet for 3 weeks, and received daily i.p. injections of the cellular stress reliever tauroursodeoxycholic acid (TUDCA, 400 mg/kg/day) or vehicle. Blood pressure was monitored by telemetry. At the end of the study, renal inflammation, apoptosis and markers of kidney damage were assessed. In ET B def rats, HSD significantly increased blood pressure (NSD vs. HSD: 131.2±1.1 vs. 153.9±5.9 mmHg, p<0.05), albuminuria, excretion of cortical tubular injury markers (NSD vs. HSD: KIM-1: 14.2±3.4 vs. 104.1±20.6 pg/day; NGAL: 43.6±17.6 vs. 215.6±27.7 pg/day; n=4-7/group; p<0.05), cortical T cell infiltration (5.7±0.3 vs. 17.4±4.5 CD3 + cells/field; p<0.05) and cortical apoptosis (4.0±1.0 vs. 18.0±4.2 TUNEL+ cells/field; n=3/group; p<0.05). No changes were seen in TG controls on HSD. TUDCA treatment prevented HSD-induced cortical damage in ET B def rats, as indicated by reduced excretion of kidney injury markers (albumin: 2.3±1.5 ng/day; KIM-1: 55.7±13.8 pg/day; NGAL: 114.2±18 pg/day; p<0.05), cortical T cell infiltration (10.8±0.5 CD3 + cells/field; p<0.05) and cortical tubular apoptosis (1.9±0.3 TUNEL+ cells/field; p<0.05). TUDCA had no effect on renal medullary apoptosis or blood pressure. Nephrin excretion remained elevated in both genotypes despite TUDCA treatment. In conclusion, loss of ET B receptor leads to exaggerated salt-mediated renal cortical damage that is attenuated by treatment with TUDCA. These results highlight the protective role of ET B receptors against the development of renal damage, especially in renal cortex. Funded by NIH T32 DK007545 to CDM and P01 HL95499 and P01 HL69999 to DMP and JSP.