Hypoxia-Inducible Factor-1Alpha Induces Apoptosis of Tubular Cells in Renal Ischemia-Reperfusion Injury via Regulating Glutathione-Specific Gamma-Glutamylcyclotransferase 1
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Kihira, Yoshitaka, Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama, Hiroshima, Japan
- Homma, Takujiro, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Fujimura, Yoshino, Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama, Hiroshima, Japan
- Matsunaga, Shinji, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Sato, Eiji, Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama, Hiroshima, Japan
- Tomita, Shuhei, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
Renal ischemia-reperfusion (I/R) is the major cause of acute renal failure in the native and transplanted kidneys. Hypoxia-inducible factor (HIF)-1α is a transcription factor for cellular adaption to hypoxia. It is shown that HIF-1α expressed in renal tubules is up-regulated during renal ischemia and contributes to recovery of the I/R induced renal injury (IRI). However, precise mechanisms for the renal protective effect of HIF-1α in the IRI remain unclear.
In the present study, we aimed to clarify the role of HIF-1α on renal IRI by employing a heterozygous HIF-1α knockout (hKO) mouse model.
Male hKO and wild type (WT) littermate mice were used for IRI model. Mice were anesthetized and the right kidney was resected. Then the left kidney was occluded with a vascular clamp at the hilus for 45 min. The clamp was removed to allow blood reperfusion.
For hypoxia-reoxygenation (H/R) treatment, human renal epithelial cell line HK2 were grown to approximately 80% confluence. The culture medium was changed to DMEM without either glucose or FBS and the cells were incubated for 24 h under 1% O2 conditions. Then, the cells were incubated in DMEM containing 10% FBS under normoxia.
Serum creatinine and blood urea nitrogen in hKO mice with IRI were higher than those in WT mice, confirming that HIF-1α contributes to repair of IRI. Apoptosis is induced in early phase of IRI in WT, while it is induced in late phase in the hKO. In hKO mice, Bcl-2/Bax ratio was increased compared with that of WT mice, indicating that Bcl-2 is a cause for the temporal difference of the apoptosis induction. We found that the pro-apoptotic factor glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) was upregulated in tubules of WT after I/R but not in those of hKO. CHAC1 knockdown in HK2 cells induced Bcl-2 upregulation after H/R treatment. These results indicate that CHAC1 regulates apoptosis induction in tubules during IRI via Bcl-2 regulation. HIF-1α knockdown with RNA interference in HK2 cells reduced CHAC1 expression after H/R treatment, indicating direct regulation of CHAC1 by HIF-1α.
Induction of apoptosis in the early phase of IRI is regulated by HIF-1α-CHAC1 axis, contributing to the repair of IRI.