Abstract: FR-PO973
KLF5 Is Upregulated via NFkB to Promote Renal Injury and Fibrosis After Cisplatin Nephrotoxicity
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Ma, Zhengwei, Augusta University Medical College of Georgia, Augusta, Georgia, United States
- Hu, Xiaoru, Augusta University Medical College of Georgia, Augusta, Georgia, United States
- Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background
Acute and chronic nephrotoxicity are the major side effects of cisplatin during chemotherapy in cancer patients. Kruppel Like Factor 5 (KLF5) is a transcriptional factor that has been implicated in renal pathogenesis such as diabetic kidney diseases. The roles and regulation of KLF5 in acute and chronic nephrotoxicity are unclear.
Methods
Changes in KLF5 expression were investigated in acute cisplatin and repeated low dose cisplatin treatment (RLDC) treated BUMPT cells in vitro and in C57BL/6 mice in vivo. Homozygous kidney proximal tubule Klf5 knockout (PT-Klf5-KO) and wild-type (WT) mice were given one injection of 20mg/kg cisplatin to examine acute kidney injury. Heterozygous Klf5 WT or KO (PT-Klf5 flox/-, with Cre- or Cre+) mice were subjected to 4 weekly injections of 7mg/kg cisplatin to examine chronic kidney injury 1 week later. The effect of KLF5 inhibition (ML-264 or KLF5 knockdown) was investigated in RLDC-treated HK2 cells. The expression of fibrotic proteins and renal injury were analyzed.
Results
Both acute cisplatin and RLDC induced KLF5 protein and mRNA in the kidney in vivo and in BUMPT cells in vitro. KLF5 was mainly induced in proximal tubules after RLDC treatment by IHC staining. KLF5 inhibition by ML-264 or KLF5 knockdown decreased the induction of fibronectin, vimentin, and profibrotic cytokine CTGF in RLDC-treated HK2 cells. There was less cleaved caspase 3 in the kidney in homozygous KLF5 knockout mice after acute cisplatin treatment. Unexpectedly, RLDC induced more KLF5 in the kidney in heterozygous PT-Klf5 KO mice compared to their WT littermates by immunoblot and IHC staining. Heterozygous KLF5 KO mice showed more renal injury, including higher KIM1, p-p53(Ser15), cleaved caspase 3 levels, and more apoptotic tubular cells. Heterozygous Klf5 KO mice showed higher BUN and lower eGFR levels than WT mice, indicating declined renal function. RLDC induced more FN, Collagen I, α-SMA, and Vimentin in the kidney in heterozygous Klf5 KO mice. Upregulation of KLF5 by RLDC is NFkb dependent in RLDC in vitro, and JSH23, an NFkB inhibitor, reduced the induction of KLF5 protein and mRNA by RLDC. Chip analysis showed that KLF5 was a direct transcriptional target of NFkB.
Conclusion
KLF5 is upregulated by acute cisplatin and RLDC treatment and promotes renal injury and renal fibrosis. The upregulation of KLF5 is NFkB dependent.
Funding
- NIDDK Support