Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury

Purvi Mehrotra, Michael Sturek, Javier A. Neyra, David P. Basile

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4951-4961
Number of pages11
JournalJournal of Clinical Investigation
Volume129
Issue number11
DOIs
StatePublished - Nov 1 2019

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Interleukin-17
Calcium Channels
Lymphocytes
Kidney
Wounds and Injuries
Reperfusion
Th17 Cells
Ischemia
Calcium
Inflammation
Intramuscular Injections
Critical Illness
Angiotensin II
Glycerol
Fibrosis
Salts
Diet
T-Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

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Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury. / Mehrotra, Purvi; Sturek, Michael; Neyra, Javier A.; Basile, David P.

In: Journal of Clinical Investigation, Vol. 129, No. 11, 01.11.2019, p. 4951-4961.

Research output: Contribution to journalArticle

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