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

Authors

Zhengwei Ma, Xiaoru Hu, Santhakumar Manicassamy, Hui Cai, Zheng Dong

Published in

Journal of the American Society of Nephrology : JASN. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

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.
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.
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.
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.

PMID:
42616595
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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