Abstract 46: Vascular Endothelium-derived Endothelin 1 Promotes Salt-induced Kidney Inflammation In Male But Not Female Mice

Endothelin 1 (ET-1), potent vasoactive and pro-inflammatory peptide, plays a criticalrole in hypertension and end-organ damage. The inflammatory response to high saltintake displays sex differences; however, if a sex difference exists in vascular ET-1inducing salt-induced kidney inflammation is unknown. We aimed to assess the role ofendothelium-derived ET-1 in promoting kidney inflammation in male and female micefed high salt. Aged-matched male and female vascular endothelial cell ET-1 knockout(VEET KO) and control floxed ET-1 (VEET fl/fl ) mice were fed 4.0% NaCl chow (HSD).After 3 weeks of HSD, kidney myeloid and lymphoid cell populations and their functionalstatus were examined by flow cytometry. In response to HSD, male VEET fl/fl mice hadsignificantly higher kidney TH17 cell numbers than female VEET fl/fl mice (IL-17A + CD4 + cell absolute count, male vs. female: 229.6±27.7 vs. 84.9±17.2, p=0.0003, n=6-10/group), indicating a substantial sex-dependent difference in kidney TH17 cellabundance. Lack of endothelium-derived ET-1 resulted in 72% reduction in renal TH17cell number in males (VEET fl/fl vs. VEET KO: 229.6±27.7 vs 64.0±64, p=0.0002), but notin females (p>0.05). Frequency of kidney IL-17A + CD4 + cells was not different betweengenotypes in females or between male and female VEET fl/fl mice. However, male VEETKO mice displayed 57% less renal IL-17A + CD4 + cells than male VEET fl/fl (respectively,0.6±0.071 vs. 1.4±0.2, p=0.0055), and 59% reduction compared to female VEET KOmice (1.4±0.2, p=0.0052). Assessment of the effects of vascular ET-1 on the innateimmune response showed that activated kidney resident macrophages(F4/80 hi CD11b + CD64 + ) were increased in male vs. female VEET fl/fl (MFI, respectively,2080±105 vs. 1672±25, p=0.0002). Lack of endothelium-derived ET-1 significantlyreduced CD64 abundance in males (p=0.012), but not females (p>0.05), whencompared to VEET fl/fl . In conclusion, endothelium-derived ET-1 is critical in promotingrenal innate and adaptive inflammatory responses in males in response to high salt, andimportant male-female differences exist in the manner by which vascular ET-1 regulateskidney inflammation in this setting. Funded by NIH F31 HL151264-0 to PAM,P01HL136267 to JSP, and K01HL145324 to CDM.