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Klf5 Is Upregulated via NF-kB to Promote Maladaptive Kidney Repair and CKD Progression
Zhengwei Ma1, Xiaoru Hu2, Santhakumar Manicassamy3
1Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA.
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.
Insights
Krüppel-like factor 5 (Klf5) drives maladaptive kidney repair after injury by promoting fibrosis and inflammation. Inhibiting Klf5, which is regulated by nuclear factor-κB (NF-κB), improves kidney function and reduces chronic kidney disease progression.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Maladaptive repair post-acute kidney injury (AKI) contributes to chronic kidney disease (CKD), but molecular drivers are unclear.
- Krüppel-like factor 5 (Klf5), a transcription factor, is elevated in kidney disease, yet its role in kidney repair is unknown.
Purpose of the Study:
- To investigate the role and regulation of Klf5 in kidney injury and repair.
- To determine if Klf5 mediates maladaptive repair and contributes to CKD development.
Main Methods:
- Klf5 expression analyzed in mouse AKI models and human CKD biopsies.
- Klf5 function studied using proximal tubule-specific Klf5 knockout mice and knockdown cells.
- Regulation by nuclear factor-κB (NF-κB) examined by ablating p65 in kidney proximal tubules.
Main Results:
- Klf5 was transcriptionally induced in proximal tubules during maladaptive repair and in human CKD.
- Klf5 knockout reduced fibrosis, inflammation, dedifferentiation, and senescence, improving kidney repair.
- NF-κB activation led to Klf5 induction, driving downstream fibrotic and inflammatory responses.
Conclusions:
- Klf5 is a critical mediator of maladaptive kidney repair and CKD development post-AKI.
- NF-κB transcriptionally up-regulates Klf5, which promotes renal inflammation, senescence, and fibrosis.
- Targeting the NF-κB/Klf5 pathway offers potential therapeutic strategies for AKI and CKD.
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