Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 11, Pages 4951-4961Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126108
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Funding
- NIH [DK063114]
- Ralph W. and Grace M. Showalter Research Trust Fund
- Indiana University Research Foundation
- Early Career Pilot Grant from the National Center for Advancing Translational Sciences (NCATS), NIH [UL1 TR001998]
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We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1(+) CD4 T cells and IL-17 expression was restricted to Orai1(+) cells. When kidney CD4(+) cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10(-7)M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17(+) cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1 - cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4(+) cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression.
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