Downregulation of KLF10 contributes to the regeneration of survived renal tubular cells in cisplatin-induced acute kidney injury via ZBTB7A-KLF10-PTEN axis

Acute kidney injury (AKI) is a common clinical dysfunction with complicated pathophysiology and limited therapeutic methods. Renal tubular injury and the following regeneration process play a vital role in the course of AKI, but the underlining molecular mechanism remains unclear. In this study, network-based analysis of online transcriptional data of human kidney found that KLF10 was closely related to renal function, tubular injury and regeneration in various renal diseases. Three classical mouse models confirmed the downregulation of KLF10 in AKI and its correlation with tubular regeneration and AKI outcome. The 3D renal tubular model in vitro and fluorescent visualization system of cellular proliferation were constructed to show that KLF10 declined in survived cells but increased during tubular formation or conquering proliferative impediment. Furthermore, overexpression of KLF10 significantly inhibited, whereas knockdown of KLF10 extremely promoted the capacity of proliferation, injury repairing and lumen-formation of renal tubular cells. In mechanism, PTEN/AKT pathway were validated as the downstream of KLF10 and participated in its regulation of tubular regeneration. By adopting proteomic mass spectrum and dual-luciferase reporter assay, ZBTB7A were found to be the upstream transcription factor of KLF10. Our findings suggest that downregulation of KLF10 positively contributed to tubular regeneration in cisplatin induced acute kidney injury via ZBTB7A-KLF10-PTEN axis, which gives insight into the novel therapeutic and diagnostical target of AKI.

Automated summary

This study found that KLF10 was closely related to renal function, tubular injury, and regeneration in various renal diseases through network-based analysis of human kidney transcriptional data. The downregulation of KLF10 in acute kidney injury (AKI) was confirmed in mouse models and correlated with tubular regeneration and AKI outcome. In vitro experiments showed that KLF10 declined in survived cells but increased during tubular formation or conquering proliferative impediment. Overexpression of KLF10 inhibited the capacity of proliferation, injury repairing, and lumen-formation of renal tubular cells, while knockdown of KLF10 promoted these processes. The PTEN/AKT pathway was validated as the downstream of KLF10 in the regulation of tubular regeneration, and ZBTB7A was identified as the upstream transcription factor of KLF10. This study provides insight into the novel therapeutic and diagnostic target of AKI.