Exploring the impact of high-altitude de-acclimatization on renal function: The roles of oxidative and endoplasmic reticulum stress in rat models

作者全名：Huang, Dong-xin; Kang, Xia; Jiang, Li-juan; Zhu, Dan -ling; Yang, Lin; Luo, Jing-ya; Yang, Meng-meng; Li, Wei; Wang, Guo-ping; Wen, Yi; Huang, Zhu; Tang, Li-jun

作者地址：[Huang, Dong-xin; Yang, Lin; Luo, Jing-ya; Tang, Li-jun] Southwest Jiaotong Univ, Coll Med, Chengdu 610031, Sichuan, Peoples R China; [Huang, Dong-xin; Kang, Xia; Yang, Lin; Luo, Jing-ya; Li, Wei; Wang, Guo-ping; Wen, Yi; Huang, Zhu; Tang, Li-jun] Gen Hosp Western Theater Command, Pancreat Injury & Repair Key Lab Sichuan Prov, Chengdu 610000, Sichuan, Peoples R China; [Huang, Dong-xin; Kang, Xia; Jiang, Li-juan; Zhu, Dan -ling; Yang, Lin; Luo, Jing-ya; Li, Wei; Wang, Guo-ping; Wen, Yi; Huang, Zhu; Tang, Li-jun] Southwest Jiaotong Univ, Affiliated Hosp, Coll Med, Chengdu 610031, Sichuan, Peoples R China; [Jiang, Li-juan; Wen, Yi; Tang, Li-jun] Gen Hosp Western Theater Command, Dept Gen Surg, Chengdu 610000, Sichuan, Peoples R China; [Zhu, Dan -ling] Westlake Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med, Hangzhou 310000, Zhejiang, Peoples R China; [Yang, Meng-meng] Chongqing Med Univ, Med Epigenet Ctr, Basic Med Collage, Chongqing 400042, Peoples R China; [Huang, Zhu] Gen Hosp Western Theater Command, Dept Hyperbar Oxygen, Chengdu 610000, Sichuan, Peoples R China

通信作者：Tang, LJ (通讯作者)，Southwest Jiaotong Univ, Coll Med, Chengdu 610031, Sichuan, Peoples R China.; Huang, Z; Tang, LJ (通讯作者)，Gen Hosp Western Theater Command, Pancreat Injury & Repair Key Lab Sichuan Prov, Chengdu 610000, Sichuan, Peoples R China.

来源：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001215962300001

JCR分区：Q3

影响因子：2.5

年份：2024

卷号：708

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：High-altitude de-acclimatization; Renal injury; Oxidative stress; Endoplasmic reticulum stress; Apoptosis

摘要：Background: High -altitude de -acclimatization (HADA) significantly impacts physiological functions when individuals acclimatize to high altitudes return to lower altitudes. This study investigates HADA 's effects on renal function and structure in rats, focusing on oxidative and endoplasmic reticulum stress as potential mechanisms of renal injury. Objective: To elucidate the pathophysiological mechanisms of renal damage in HADA and evaluate the efficacy of antioxidants Vitamin C (Vit C) and tauroursodeoxycholic acid (TUDCA) in mitigating these effects. Methods: 88 male Sprague-Dawley rats were randomly divided into a control group, a high -altitude (HA) group, a high -altitude de -acclimatization (HADA) group, and a treatment group. The control group was housed in a sea level environment (500 m), while the HA, HADA, and treatment groups were placed in a simulated high -altitude chamber (5000 m) for 90 days. After this period, the HA group completed the modeling phase; the HADA group was further subdivided into four subgroups, each continuing to be housed in a sea level environment for 3, 7, 14, and 30 days, respectively. The treatment group was split into the Vit C group, the TUDCA group, and two placebo groups, receiving medication for 3 consecutive days, once daily upon return to the sea level. The Vit C group received 100 mg/kg Vit C solution via intravenous injection, the TUDCA group received 250 mg/kg TUDCA solution via intraperitoneal injection, and the placebo groups received an equivalent volume of saline similarly. Serum, urine, and kidney tissues were collected immediately after the modeling phase. Renal function and oxidative stress levels were assessed using biochemical and ELISA methods. Renal histopathology was observed with H &E, Masson 's trichrome, PAS, and PASM staining. Transmission electron microscopy was used to examine the ultrastructure of glomeruli and filtration barrier. TUNEL staining assessed cortical apoptosis in the kidneys. Metabolomics was employed for differential metabolite screening and pathway enrichment analysis. Results: Compared to the control and HA groups, the HADA 3 -day group (HADA-3D) exhibited elevated renal function indicators, significant pathological damage, observable ultrastructural alterations including endoplasmic reticulum expansion and apoptosis. TUNEL-positive cells significantly increased, indicating heightened oxidative stress levels. Various differential metabolites were enriched in pathways related to oxidative and endoplasmic reticulum stress. Early intervention with Vit C and TUDCA markedly alleviated renal injury in HADA rats, significantly reducing the number of apoptotic cells, mitigating endoplasmic reticulum stress, and substantially lowering oxidative stress levels. Conclusion: This study elucidates the pivotal roles of oxidative and endoplasmic reticulum stress in the early -stage renal injury in rats undergoing HADA. Early intervention with the Vit C and TUDCA significantly mitigates renal damage caused by HADA. These findings provide insights into the pathophysiological mechanisms of HADA and suggest potential therapeutic strategies for its future management.

基金机构：National Clinical Key Specialty in General Surgery in China [41732113]; Pancreatic Injury and Repair Key Laboratory of Sichuan Province [41732152]; General Project of Applied Basic Research of The General Hospital of Western Theater Command [CLB19J050]; General Project of The General Hospital of Western Theater Command [2021-XZYG-C30]; Science and Technology Department of Sichuan Province [2023YFS0082]

基金资助正文：The authors would like to thank all members of our laboratory for their work. This research was supported by the National Clinical Key Specialty in General Surgery in China (No. 41732113) , Pancreatic Injury and Repair Key Laboratory of Sichuan Province (No. 41732152) , the General Project of Applied Basic Research of The General Hospital of Western Theater Command (No. CLB19J050) , the General Project of The General Hospital of Western Theater Command (No. 2021-XZYG-C30) and the funding of Science and Technology Department of Sichuan Province (2023YFS0082) .