Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, 050017, Shijiazhuang, Hebei, China.
Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, 050017, Shijiazhuang, Hebei, China; Hebei Key Laboratory of Metabolic Diseases, Clinical Medicine Research Center, Hebei General Hospital, 050051, Shijiazhuang, Hebei, China.
Nitric Oxide. 2024 Nov 1;152:11-18. doi: 10.1016/j.niox.2024.09.003. Epub 2024 Sep 11.
To investigate the protective mechanisms of hydrogen sulfide (HS) in sepsis-induced acute kidney injury (SAKI), we conducted an in vivo study using a SAKI mouse model induced by intraperitoneal lipopolysaccharide (LPS) injection. Following 6 h of LPS injection, levels of tumor necrosis factor-alpha (TNF-α) and blood urea nitrogen (Bun) were significantly elevated in mouse plasma. In the kidneys of SAKI mice, expression of HS-generating enzymes cysteinyl-tRNA synthetase (CARS), cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) was markedly downregulated, while glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase (p-PERK/PERK), and B-cell lymphoma-2 recombinant protein X/B-cell lymphoma-2 (Bax/Bcl2) expression was significantly upregulated. HS improved renal function and attenuated renal histopathological changes in SAKI mice, thereby alleviating LPS-induced endoplasmic reticulum stress (ERS). Additionally, it inhibited the expression of p-PERK/PERK and Bax/Bcl2. After inhibiting CSE activity with dl-propargylglycine (PPG i. p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous HS influences the pathogenesis of SAKI, while exogenous HS protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.
为了研究硫化氢（HS）在脂多糖（LPS）诱导的急性肾损伤（SAKI）中的保护机制，我们采用腹腔注射 LPS 建立 SAKI 小鼠模型进行了一项体内研究。在 LPS 注射 6 小时后，小鼠血浆中肿瘤坏死因子-α（TNF-α）和血尿素氮（Bun）的水平显著升高。在 SAKI 小鼠的肾脏中，HS 生成酶半胱氨酸-tRNA 合成酶（CARS）、胱硫醚γ-裂解酶（CSE）和胱硫醚β-合酶（CBS）的表达明显下调，而葡萄糖调节蛋白 78（GRP78）、激活转录因子 6（ATF6）、磷酸化蛋白激酶 R 样内质网激酶/蛋白激酶 R 样内质网激酶（p-PERK/PERK）和 B 细胞淋巴瘤-2 重组蛋白 X/B 细胞淋巴瘤-2（Bax/Bcl2）的表达显著上调。HS 改善了 SAKI 小鼠的肾功能，减轻了肾脏组织学变化，从而减轻了 LPS 诱导的内质网应激（ERS）。此外，它还抑制了 p-PERK/PERK 和 Bax/Bcl2 的表达。用 dl-丙炔甘氨酸（PPG i.p.）抑制 CSE 活性后，LPS 诱导的 AKI 小鼠的肾组织病理学进一步加重，导致 PERK/Bax-Bcl2 通路的激活增强。我们的研究结果表明，内源性 HS 影响 SAKI 的发病机制，而外源性 HS 通过抑制 PERK/Bax-Bcl2 通路来保护 LPS 诱导的 AKI，该通路涉及 ERS。
