Figure 1. Major events during Orai1-mediated Th17 differentiation in AKI.

(A) In resting CD4⁺ T cells, Orai1 is in a closed confirmation and Ca²⁺ is confined to the ER lumen. Following IR, Orai1 expression increases. With subsequent increase in intracellular Ca²⁺, RORγT activity and IL-17 production drives Th17 differentiation and AKI pathogenesis. Simultaneously, antigen binding to the TCR triggers ER Ca²⁺ release, likely via the PLC/IP3 pathway. STIM1, sensing loss of ER Ca²⁺, translocates to the plasma membrane and activates CRAC protein, resulting in Orai1 opening. Exposure to high Ang II and Na⁺ following AKI reactivates the Th17 response in predominantly Orai1⁺ cells and sustains inflammation to drive AKI to CKD. (B) CRAC inhibitors, such as YM58483/BTP2, block Ca²⁺ influx through Orai1 and may protect from AKI and limit the AKI-to-CKD transition.