Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Critical Care Medicine, Center of Critical Nephrology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
FASEB J. 2022 Apr;36(4):e22228. doi: 10.1096/fj.202101555RR.
Tissue inhibitor of metalloproteinase 2 (TIMP2) has been recognized as an important biomarker for predicting acute kidney injury (AKI) because of its involvement in the process of inflammation and apoptosis in septic AKI. Endoplasmic reticulum (ER) stress, a condition of disrupted ER homeostasis, is implicated in multiple pathophysiological processes, including kidney disease. Herein, we investigated the correlation between ER stress and septic AKI and further explored how TIMP2 regulated ER stress-mediated apoptosis. To assess the role of TIMP2 in sepsis-induced AKI, we used a cecal ligation and puncture (CLP) model in mice with tubule-specific deficiency of TIMP2 (Ksp-Cre/TIMP2 ) and their wild-type counterparts. Compared to the wild-type mice, TIMP2-deficient mice demonstrated lower serum creatinine levels and decreased ER stress-mediated apoptosis when subjected to CLP. Interestingly, in human kidney (HK-2) cells, overexpression of TIMP2 caused ER stress, whereas TIMP2 knockdown attenuated lipopolysaccharide-induced ER stress and apoptosis. TIMP2 interacted with the binding immunoglobulin protein, an ER chaperone, and facilitates its extracellular secretion, thereby triggering ER stress. This study identified that the deletion of TIMP2 in mouse tubules mitigated sepsis-induced AKI by inhibiting ER stress-mediated apoptosis, which might be a potential therapeutic strategy to alleviate renal injury.
金属蛋白酶组织抑制剂 2（TIMP2）已被认为是预测急性肾损伤（AKI）的重要生物标志物，因为它参与了脓毒症 AKI 中的炎症和细胞凋亡过程。内质网（ER）应激是 ER 稳态失调的一种情况，与包括肾脏疾病在内的多种病理生理过程有关。在此，我们研究了 ER 应激与脓毒症 AKI 之间的相关性，并进一步探讨了 TIMP2 如何调节 ER 应激介导的细胞凋亡。为了评估 TIMP2 在脓毒症诱导的 AKI 中的作用，我们使用了肾小管特异性缺乏 TIMP2（Ksp-Cre/TIMP2）的小鼠和其野生型对照的盲肠结扎和穿孔（CLP）模型。与野生型小鼠相比，TIMP2 缺陷型小鼠在接受 CLP 后血清肌酐水平较低，且 ER 应激介导的细胞凋亡减少。有趣的是，在人肾（HK-2）细胞中，TIMP2 的过表达导致 ER 应激，而 TIMP2 的敲低则减弱了脂多糖诱导的 ER 应激和细胞凋亡。TIMP2 与结合免疫球蛋白蛋白（一种 ER 伴侣）相互作用，并促进其细胞外分泌，从而引发 ER 应激。这项研究表明，在小鼠肾小管中缺失 TIMP2 通过抑制 ER 应激介导的细胞凋亡减轻了脓毒症引起的 AKI，这可能是一种减轻肾脏损伤的潜在治疗策略。
