Jindi Ni1, Lijing Jiang1, Guofeng Shen1, Zhuye Xia1, Lu Zhang1, Jing Xu2, Quanxia Feng1, Hongping Qu3, Fulin Xu4, Xiang Li5. 1. Department of Critical Care Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China. 2. General Practice, Shanghai Meilong Community Health Service Center, Shanghai 201199, China. 3. Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. 4. Department of Neurosurgery, Minhang Hospital, Fudan University, Shanghai 201199, China. Electronic address: ruileji6763372@163.com. 5. Department of Critical Care Medicine, Minhang Hospital, Fudan University, Shanghai 201199, China. Electronic address: lixiang0105200@163.com.
Abstract
AIMS: Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) shows high mortality. Hydrogen sulfide (H2S) is essential for regulating kidney function. This study explored the role and mechanism of H2S in I/R-induced AKI. MATERIALS AND METHODS: I/R-induced mouse model and hypoxia/reoxygenation (H/R)-induced HK2 cell model of AKI were established and treated with NaHS (H2S donor), MCC950 (NLRP3 inhibitor) or DL-Propargylglycine (PAG, CSE inhibitor). Serum creatinine (Cr) and blood urea nitrogen (BUN) were measured to evaluate kidney function. The pathological changes of kidney tissues were detected. H2S level and H2S synthetase activity in kidney tissues were detected. Pyroptosis was assessed by pyroptotic cell numbers and pyroptosis-related protein levels determination. HK-2 cell viability and apoptosis were measured. NLRP3 protein level was detected. The role of NLRP3/Caspase-1 was verified in vivo and in vitro after MCC950 or PAG intervention. KEY FINDINGS: I/R-induced mice showed elevated levels of serum Cr and BUN, and obvious pathological changes, including severe tubular dilatation, tubular cell swelling, tubular epithelial cell abscission, tubular cell necrosis and inflammatory cell infiltration. H2S level and H2S synthetase activity were decreased. Increasing the level of H2S by NaHS improved the pathological changes of kidney tissues and limited the number of pyroptotic cells. In vitro, NaHS could reverse H/R-induced cell injury. H2S suppressed cell pyroptosis and kidney injury via inhibiting the NLRP3/Caspase-1 axis. SIGNIFICANCE: We highlighted that H2S prevented cell pyroptosis via suppressing the NLRP3/Caspase-1 axis, thereby inhibiting I/R-induced AKI. These findings may confer novel insights for the clinical management of I/R-induced AKI.
AIMS: Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) shows high mortality. Hydrogen sulfide (H2S) is essential for regulating kidney function. This study explored the role and mechanism of H2S in I/R-induced AKI. MATERIALS AND METHODS: I/R-induced mouse model and hypoxia/reoxygenation (H/R)-induced HK2 cell model of AKI were established and treated with NaHS (H2S donor), MCC950 (NLRP3 inhibitor) or DL-Propargylglycine (PAG, CSE inhibitor). Serum creatinine (Cr) and blood ureanitrogen (BUN) were measured to evaluate kidney function. The pathological changes of kidney tissues were detected. H2S level and H2S synthetase activity in kidney tissues were detected. Pyroptosis was assessed by pyroptotic cell numbers and pyroptosis-related protein levels determination. HK-2 cell viability and apoptosis were measured. NLRP3 protein level was detected. The role of NLRP3/Caspase-1 was verified in vivo and in vitro after MCC950 or PAG intervention. KEY FINDINGS: I/R-induced mice showed elevated levels of serum Cr and BUN, and obvious pathological changes, including severe tubular dilatation, tubular cell swelling, tubular epithelial cell abscission, tubular cell necrosis and inflammatory cell infiltration. H2S level and H2S synthetase activity were decreased. Increasing the level of H2S by NaHS improved the pathological changes of kidney tissues and limited the number of pyroptotic cells. In vitro, NaHS could reverse H/R-induced cell injury. H2S suppressed cell pyroptosis and kidney injury via inhibiting the NLRP3/Caspase-1 axis. SIGNIFICANCE: We highlighted that H2S prevented cell pyroptosis via suppressing the NLRP3/Caspase-1 axis, thereby inhibiting I/R-induced AKI. These findings may confer novel insights for the clinical management of I/R-induced AKI.
Authors: Chenxia Juan; Ye Zhu; Yan Chen; Yan Mao; Yan Zhou; Weiwei Zhu; Xufang Wang; Qian Wang Journal: Bioengineered Date: 2022-05 Impact factor: 6.832