HIF-mediated regulation of glutathione-specific γ-glutamyl cyclotransferase 1 contributes to tubular cell death in renal ischemia-reperfusion injury.

Abstract

Renal ischemia-reperfusion (I/R) remains a leading cause of acute renal failure in both native and transplanted kidneys. Hypoxia-inducible factor (HIF)-1α is a protective factor against renal I/R injury (rIRI). However, the downstream mechanisms through which HIF-1α exerts its protective effects in rIRI remain to be fully elucidated. rIRI was induced in heterozygous HIF-1α knockout (hKO) mice. To establish an in vitro model of rIRI, a human tubular cell line (HK2) was subjected to hypoxia-reoxygenation (H/R). rIRI-induced hKO mice exhibited elevated serum creatinine levels compared with rIRI-induced wild-type (WT) mice. Furthermore, tubular cell death was observed earlier in WT mice during the initial phase of I/R, whereas it was reduced in hKO mice. Phagocytosis of damaged tubular cells by macrophages was diminished in hKO mice, suggesting that the clearance of cellular debris plays a critical role in renal tissue repair and regeneration. Furthermore, glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a known cell death inducer, was upregulated in the tubular cells of WT mice but not hKO mice following I/R. The overexpression of CHAC1 in HK2 cells induced cell death, whereas siRNA-mediated CHAC1 knockdown attenuated cell death in HK2 cells subjected to H/R. These findings collectively suggest that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI. Our findings indicate that controlled cell death induction is essential for rIRI recovery. CHAC1, a key factor in this process, is a potential therapeutic target for rIRI.Here, we reported that HIF-1α upregulates glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a regulator of cell death and oxidative stress, in rIRI. Our results suggested that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI, and the controlled tubular cell death induced by CHAC1 is essential for rIRI recovery. This proposes novel mechanisms underlying rIRI recovery.