H2S alleviates renal ischemia and reperfusion injury by suppressing ERS-induced autophagy

Background: Ischemia/reperfusion injury (IRI) can lead to acute kidney injury and result in high disability and mortality rates. Cystathionine γ-lyase (CSE)-produced hydrogen sulfide (H₂S) has been confirmed to play a protective role in renal IRI. While Autophagy is involved in renal IRI, its role in the regulation by endoplasmic reticulum stress (ERS) has not been considered. Our study explored the role of CSE/H₂S in protecting against renal IRI by regulating ERS-induced Autophagy.

Methods: C57/BL6 mice were subjected to 30-min renal ischemia followed by .24-h reperfusion injury (IRI). The H₂S donor sodium hydrosulfide hydrate (NaHS) or the CSE inhibitor D,L-propargylglycine (PAG) was injected intraperitoneally (i.p) into the mice. Serum creatinine and urea nitrogen levels were analyzed to evaluate renal function. Renal tubule epithelial cell damage was measured by HE and PAS staining. ERS and microtubule-associated protein LIGHT chain 3 (LC3) Autophagy (LC3-I to LC3-II conversion) were analyzed by using western blotting.

Results: In a C57/BL6 mouse model of acute renal IRI, the application of IRI impaired the renal function, which was accompanied by elevated serum creatinine (P < 0.001) and urea nitrogen levels (P < 0.001). While NaHS pretreatment dramatically attenuated renal IRI, PAG administration exacerbated renal IRI (P < 0.001). Furthermore, NaHS treatment inhibited the ERS-induced increased LC3II/I protein ratio (P < 0.001); increased Beclin-1 protein expression (P < 0.001); PAG pretreatment exacerbated the effects of ERS on both the LC3II/I ratio (P < 0.001) and the Beclin-1 protein expression (P < 0.001).

Conclusions: Our results suggest that the CSE/H₂S system is an important therapeutic target for protecting against renal IRI, and it may protect renal tubule epithelial cells from IRI by suppressing ERS-induced Autophagy.

Autophagy; ERS; Hydrogen sulfide; Renal ischemia and reperfusion injury; Renal transplantation.