Macrophage-Derived Type I IFN, Renal Tubular Epithelial Cell Polyploidization, and AKI-to-CKD Transition

Background: Acute kidney injury (AKI) is recognized as a common risk factor for chronic kidney disease (CKD). Renal tubular epithelial cell polyploidization after AKI is closely associated with maladaptive repair, while the regulatory and molecular mechanisms remain poorly understood. Here, we set out to investigate the mechanism of tubular epithelial cell polyploidization and their role in the AKI-to-CKD transition. Methods: The change characters of polyploid tubular epithelial cells and macrophages after AKI were detected by flow cytometry and immunofluorescence. The underlying mechanism was explored by RNA-sequencing analysis, immunofluorescence and western blot. The role of tubular epithelial cell polyploidization in the AKI-to-CKD transition was evaluated by transgenic mice and drug interventions. Results: We discovered that tubular epithelial cells underwent polyploidization after AKI and polyploid tubular epithelial cells exhibited greater fibrotic phenotypes than non-polyploid cells. Furthermore, we revealed an upregulated IFN-β response feature within tubular epithelial cells after AKI, and identified that macrophage-derived IFN-β bound to IFN-I receptor 1 (IFNAR1) of tubular epithelial cells and induced their polyploidization. Mechanistically, IFN-β, secreted by macrophages through activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, acted on tubular epithelial cells and facilitated inorganic pyrophosphatase binding to Yes-associated protein (YAP), which mediated YAP dephosphorylation and subsequent nuclear translocation, culminating in p21 expression and polyploidization. Importantly, delayed blockade of the IFN-β response and pharmacological inhibition of STING or YAP activation on day 4 after AKI significantly attenuated persistent tubular epithelial cell polyploidization and AKI-induced kidney fibrosis. Conclusions: Macrophage-derived IFN-β contributed to tubular epithelial cell polyploidization by regulating inorganic pyrophosphatase/YAP signaling pathway-mediated p21 expression and further promoted AKI-to-CKD transition.