Dexmedetomidine attenuates renal fibrosis via α2-adrenergic receptor-dependent inhibition of cellular senescence after renal ischemia/reperfusion

Abstract

BackgroundRenal ischemia/reperfusion (IR) can induce acute kidney injury (AKI), which often progresses to chronic kidney disease (CKD). Dexmedetomidine (Dex), a highly selective α2 adrenergic receptor (α2-AR) agonist, protects against acute renal IR-induced injury. However, the effects of Dex on the transition of AKI to CKD remain unclear. Therefore, we investigated the mechanisms of Dex on renal fibrosis. MethodsAdult male C57BL/6 mice were pretreated with Dex, a specific α2A-adrenergic receptor (AR) blocker (BRL-44408), or a cell senescence inhibitor (rapamycin) in a surgical bilateral renal IR model. The diagnoses of AKI and chronic renal fibrosis were performed by histopathological staining and western blotting. Histopathological changes, cell senescence, tubular fibrotic markers, and the expression of inflammatory factors were studied. ResultsPretreatment with Dex alleviated renal IR-induced AKI and chronic tubulointerstitial fibrosis in later stages. Similar to the effects of rapamycin, pretreatment with Dex also decreased the number of senescent tubular cells and weakened the protein expression of senescence-associated markers such as p53, p21, and p16. Furthermore, the expression of inflammatory markers was also decreased in Dex-treated IR mice; and these protective effects of Dex could be abolished by treatment with the specific α2A-AR blocker, BRL-44408. ConclusionsThe administration of a single dose of Dex protects against AKI and CKD. Dex inhibits tubular cell senescence and inflammation as well as improves renal fibrosis to moderate the AKI-to-CKD transition. The renal protective potential of Dex may provide a novel treatment strategy for high-risk renal injury patients.