CXCR2 inhibits tubular autophagy to promote acute kidney injury via regulating ERK1/2/ NF-κB p65/ATG5 signaling axis

Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. However, its pathogenesis is still incompletely understood. Increased expression of CXCR2 has been reported in acute kidney injury (AKI), but its regulatory mechanism remains unclear. Here we found that increased CXCR2 in tubular cells, as seen in ischemia-reperfusion injury (IRI)-induced or cisplatin-induced AKI, was colocalized with apoptosis and autophagy related indicators. In human AKI, CXCR2 was found present in tubular cells in kidney biopsy tissue and positively correlated with the severity of AKI. Tubular-specific CXCR2 knockout mice decreased the severity of IRI-induced AKI as characterized by lower kidney injury, interstitial inflammation, apoptosis and higher renal function. Furthermore, analysis of murine nephrotoxic AKI transcriptomics indicated autophagy as highly upregulated and ERK1/2/NF-κB signaling downregulated. On the other hand, overexpression CXCR2 with pFlag-CXCR2 plasmid aggravated renal function damage by regulating ERK1/2/ NF-κB p65-mediating autophagy in IRI-induced or cisplatin-induced AKI mice model. Treatment of AZD5069 ameliorated apoptosis and promoted autophagy in the AKI model. siCXCR2 significantly promoted autophagy and inhibited apoptosis and injury in cultured H/R treated-HKC-8 cells. Mechanistically, p-ERK1/2 promoted p-p65 transferred into nucleus, resulting in p65 directly binding to the promoter region of ATG5 gene which is an important molecule in the regulation of autophagy in vitro. Thus, our findings demonstrate that deletion or inhibition CXCR2 increasing autophagy by attenuating tubular injury, inflammation, and apoptosis in AKI. Hence, our study identifies CXCR2 as a critical regulator of autophagy and provides a potent strategy for preventing tubular injury in AKI.