The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/ reperfusion injury

Emerging evidence indicates that retinoid-related orphan receptor (ROR)α, a member of the ROR nuclear receptor subfamily, mediates key cellular adaptions to hypoxia and contributes to the pathophysiology of many disease states. However, the effects of RORα in renal ischemia/reperfusion (I/R) injury remain unclear. Wild-type (WT) C57 black 6 (C57BL/6) mice and RORα-deficient stagger [ROR(sg/sg)] mice and their WT litter-mates were used for in vivo studies. The renal I/R injury model was induced by bilateral renal pedicle clamping for 35 min. Human proximal tubule cell line cells were treated with hypoxia (1% oxygen) to establish the cell hypoxia/reoxygenation (H/R) model. We investigated the renal expression and biologic function of RORα, and we found that RORα was significantly down-regulated after renal I/R injury. ROR(sg/sg) mice displayed dramatically augmented renal dysfunction and morphologic damage compared with WT mice at 24 h post-I/R. Further study revealed that the detrimental effects of RORα deficiency were attributable to tubular epithelial cell apoptosis and, consequently, renal inflammation and oxidative stress. The proapoptotic effect of RORα deficiency was associated with aggravated mitochondrial dysfunction in renal tubular cells after I/R. However, pretreatment of C57BL/6 mice with the RORα agonist SR1078 ameliorated I/R-induced renal dysfunction and damage and elicited a concomitant decrease in tubular epithelial cell apoptosis. In summary, our study provides experimental evidence showing that RORα is a novel endogenous protector against renal I/R injury and that ROR-α activation is a promising therapeutic strategy for the prevention of acute kidney injury.—Cai, J., Jiao, X., Fang, Y., Yu, X., Ding, X. The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/reperfusion injury. FASEB J. 33, 5704–5715 (2019). www.fasebj.org