Krüppel-Like Factor 5 Is Upregulated by NF-κB To Promote Maladaptive Kidney Repair and CKD Progression

KEY POINTS: Krüppel-like factor 5 was transcriptionally induced in renal proximal and nonproximal tubular cells in mouse models of maladaptive kidney repair and human CKD biopsies. NF-κB mediated Krüppel-like factor 5 induction in maladaptive kidney repair by directly binding to its gene promoter. Upon induction, Krüppel-like factor 5 contributed to maladaptive kidney repair and CKD development by inducing chronic inflammation, cellular senescence, and fibrosis. BACKGROUND: Maladaptive repair following AKI 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 postinjury kidney repair are unknown. METHODS: Klf5 expression was analyzed in C57BL/6 mice after unilateral ischemia/reperfusion, repeated low-dose cisplatin, and unilateral ureteral obstruction in vivo in human CKD biopsies and in TGF β -, TNF α -, 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 models in vivo . To examine the regulation by 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 postinjury 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 by promoter binding. CONCLUSIONS: The results demonstrated Klf5 as a critical mediator of maladaptive repair and CKD development after AKI. Mechanistically, Klf5 was transcriptionally upregulated by NF-κB. Upon induction, Klf5 contributed to renal inflammation, senescence, and fibrosis, highlighting potential therapeutic targets.