Wnt/ß-catenin/ATF3 signaling promotes AKI to CKD progression by regulating mitophagy in mice [HKC-8]

Sustained activation of Wnt/ß-catenin signaling has been shown to promote AKI to CKD progression. However, its underlying mechanisms remain largely unclear. In this study, we investigated this issue via unilateral ischemia/reperfusion injury in mice and hypoxia/reoxygenation (H/R) in HKC-8 cells. Both in vitro and in vivo, overexpression of Wnt1 promoted mitochondrial dynamics and mitophagy damage. Furthermore, we revealed that ATF3 not only is a transcriptional target of canonical Wnt/ß-catenin signaling but is also an important pathogenic mediator of kidney disease. ATF3 was expressed in various CKD animal models, including UUO, UIRI, ADR and 5/6NX. In vitro, exogenous ATF3 induced mitochondrial dynamics and mitophagy, and silenced ATF3 expression protected mitochondrial function. Finally, compared with normal individuals, patients with various kidney diseases presented markedly elevated levels of ATF3. In addition, ATF3 levels are closely correlated with renal injury markers and renal fibrosis area in patients. Thus, these results suggest that Wnt/ß-catenin/ATF3 signaling activation promotes AKI to CKD progression by regulating mitochondrial dynamics and mitophagy. ATF3 can serve as a promising potential biomarker for AKI to CKD progression. Overall design: In the HKC-8 cells, the cells transfected with either p-Wnt-1 or pcDNA3 were sequenced. The cells transfected with p-Wnt-1 and treated with KP6 were also sequenced.