Orai1: A New Therapeutic Target for the Acute Kidney Injury-to-Chronic Kidney Disease Transition

Abstract

This review focuses on the potential mediation in the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition by lymphocytes. We highlight evidence that lymphocytes, particularly Th17 cells, modulate the severity of both acute injury and chronic kidney disease. Th17 cells are strongly influenced by the activity of the store-operated Ca2+channel Orai1, which is upregulated on lymphocytes in animal models of AKI. Inhibition of this channel attenuates both acute and chronic kidney injury in rodent models. In addition, Oria1+ cells are increased in peripheral blood of patients with AKI. Similarly, peripheral blood cells manifest an early and sustained increase in Orai1 expression in a rat model of ischemia/reperfusion, suggesting that blood cell Orai1 may represent a marker informing potential Th17 activity in the setting of AKI or the AKI-to-CKD transition.

Keywords: Acute renal injury; CKD; Inflammation.

Figure 1.. Activation and differentiation of Th17 cells in the setting of renal injury and potential influence of salt.

Th17 cell differentiation and IL17 activation occur secondary to TCR activation. Activation of STAT3 is required for induction of the transcription factor RORγT, which mediates transcription of the signature cytokine, IL17. The process appears to be dependent on activation of the SOCC Orai1, which is initially activated by ER depletion of Ca²⁺, which is sensed by Stim1. The sustained elevation of Ca2+ mediated by Orai1 activates NFAT dephosphorylation and further drives IL17 expression. Orai1 is also activated by a high salt environment, possibly resulting from SGK signaling, which may further amplify Th17 activity in the setting of elevated dietary sodium intake. Reprinted from reference [7], with permission of the Korean Society of Nephrology.

Figure 2:. Rapid and sustained increase in Orai1 expression in peripheral blood of rats.

Sprague-Dawley (~250-300 g) rats were subjected to 40 minutes of bilateral renal ischemia and reperfusion for 6 hours or 40 minutes of unilateral renal ischemia and reperfusion for 35 days. Total peripheral blood cells were stained with anti Orai1 antibodies similar to procedure described in reference [12] and subjected to FACS analysis. Data are expressed as % Orai1+ cells. I/R caused a significant increase in Orai1+ cells both 6 hours and 35 days after ischemia (* indicates P <0.05 vs sham by ANOVA and Tukey’s post-hoc test).