Klf5 Is Upregulated via NF-kB to Promote Maladaptive Kidney Repair and CKD Progression

BACKGROUND: Maladaptive repair following acute kidney injury leads to CKD, but the underlying molecular drivers remain incompletely understood. Krüppel-like factor 5 (Klf5), a zinc finger transcription factor, is upregulated in kidney diseases. However, its role and regulation in post-injury kidney repair are unknown. METHODS: Klf5 expression was analyzed in C57BL/6 mice after unilateral ischemia/reperfusion (I/R), repeated low-dose cisplatin (RLDC), and unilateral ureteral obstruction (UUO) in vivo, in human CKD biopsies, and in TGFβ-, TNFα, and RLDC-treated kidney proximal tubule cells in vitro. The role of Klf5 was investigated using Klf5 knockdown proximal tubular cells in vitro and proximal tubule-specific Klf5 knockout mouse model in vivo. To examine the regulation by nuclear factor-κB (NF-κB), p65 (RelA, a key component of the NF-κB complex) was specifically ablated from kidney proximal tubule cells in mice. RESULTS: Klf5 was transcriptionally induced in renal proximal tubular cells in mouse models of maladaptive kidney repair and in human CKD biopsies. Proximal tubule-specific Klf5 knockout significantly reduced fibrosis, inflammation, dedifferentiation, and cellular senescence in post-injury kidneys, leading to improved kidney repair. Genetic or pharmacologic inhibition of NF-κB attenuated Klf5 expression and downstream fibrotic and inflammatory responses. NF-κB was further proved to transactivate Klf5 via promoter binding. CONCLUSIONS: The results demonstrated Klf5 as a critical mediator of maladaptive repair and CKD development after AKI. Mechanistically, Klf5 was transcriptionally up-regulated via NF-κB. Upon induction, Klf5 contributed to renal inflammation, senescence, and fibrosis, highlighting potential therapeutic targets.