Abstract: SA-PO1183
KLF5 Is Upregulated via NFkB to Promote Maladaptive Kidney Repair after Ischemia-Reperfusion Injury
Session Information
- CKD: Mechanisms - 3
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Ma, Zhengwei, Augusta University Medical College of Georgia, Augusta, Georgia, United States
- Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background
Kruppel Like Factor 5 (KLF5) is a transcriptional factor that has been implicated in the pathogenesis of diabetic kidney disease and lupus nephritis. However, its role and regulation in acute kidney injury (AKI) and post-AKI kidney repair are unknown.
Methods
KLF5 expression was analyzed in C57BL/6 mice after renal ischemia-reperfusion injury (IRI) in vivo and TGFβ-treated kidney proximal tubule cells in vitro. A proximal tubule-specific Klf5 knockout (PT-Klf5-KO) mouse model was established to examine the role of KLF5 in AKI and post-AKI repair. In vitro, the effect of klf5 knockdown was investigated in TGFβ-treated proximal tubular cells.
Results
KLF5 was induced by IRI in the kidney and the induction was mainly in proximal tubule cells in immunohistochemistry staining. Renal IRI was more severe in PT-Klf5-KO mice than in wild-type mice as shown by BUN and creatinine levels and the percentage of injured tubules, suggesting a protective role of KLF5 at the acute injury phase. However, PT-Klf5-KO mice showed a significantly better kidney repair after renal IRI. At 2 weeks after renal IRI, PT-Klf5-KO mice had higher eGFR, lower BUN and serum creatinine, and markedly less renal fibrosis. Klf5 KO mice also showed less senescence as indicated by less β-Gal staining and P16 expression. In addition, PT-Klf5 KO decreased TNFα and Cxcl2 mRNA expression and macrophage infiltration in the kidneys. KLF5 was also induced in TGFβ-treated proximal tubular cells, and knockdown of Klf5 decreased the induction of fibronectin and profibrotic cytokines in these cells. The induction of KLF5 during renal IRI was attenuated in proximal tubule-specific NF-kB/P65 knockout mice. It was also suppressed by the pharmacological inhibitor of NF-kB, JSH23. Chromatin immunoprecipitation (ChIP) assay further showed that KLF5 was a direct transcriptional target of NF-kB.
Conclusion
KLF5 is upregulated via NF-kB during renal IRI and post-injury kidney repair. While KLF5 may play a protective role against acute injury, it promotes maladaptive kidney repair by inducing renal inflammation, senescence, fibrosis, and deterioration of kidney function.
Funding
- NIDDK Support