Aouichat Samira, Navarro-Alarcon Miguel, Alarcón-Guijo Pablo, Salagre Diego, Ncir Marwa, Zourgui Lazhar, Agil Ahmad
Department of Pharmacology, Biohealth Institute and Neurosciences Institute, School of Medicine, University of Granada, 18016 Granada, Spain.
Team of Cellular and Molecular Physiopathology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, El Alia, Algiers 16111, Algeria.
Pharmaceuticals (Basel). 2021 Mar 8;14(3):232. doi: 10.3390/ph14030232.
Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C-ZL rats, higher ER stress response associated with impaired renal morphology was observed in C-ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho-protein kinase RNA-like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho-c-jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.
肥胖和糖尿病与肾脏疾病患病率的增加有关。内质网应激最近在肥胖和糖尿病相关肾脏疾病的发病机制中变得越来越重要。褪黑素是一种重要的具有抗肥胖作用的天然生物活性化合物。此前，我们的研究小组表明，在糖尿病肥胖诱导的肾损伤大鼠模型中，褪黑素给药的肾脏保护作用与恢复线粒体裂变/融合平衡及功能有关。本研究旨在进一步探讨褪黑素是否能在肥胖和糖尿病条件下抑制肾脏内质网（ER）应激反应及下游未折叠蛋白反应激活。将 Zucker 糖尿病肥胖（ZDF）大鼠和瘦的同窝大鼠（ZL）分别口服补充褪黑素（10 mg/kg 体重（BW）/天）（M-ZDF 和 M-ZL）或赋形剂（C-ZDF 和 C-ZL），持续 17 周。对内质网应激相关标志物进行蛋白质印迹分析并评估肾脏形态。与 C-ZL 大鼠相比，C-ZDF 大鼠中观察到与肾脏形态受损相关的更高内质网应激反应。补充褪黑素可减轻 ZDF 大鼠的肾脏内质网应激反应，通过降低葡萄糖调节蛋白 78（GRP78）、肌醇需要酶 1α（IRE1α）和 ATF-6 水平，但对磷酸化蛋白激酶 RNA样内质网激酶（PERK）水平无影响。此外，补充褪黑素还抑制了内质网应激介导的凋亡途径，表现为促凋亡蛋白磷酸化 c-Jun 氨基末端激酶（JNK）、Bax 和裂解的半胱天冬酶-3 减少，以及 B 细胞淋巴瘤（Bcl）-2 蛋白上调。这些改善与肾脏结构恢复有关。综上所述，我们的研究结果表明，褪黑素至少部分通过抑制内质网应激和相关的促凋亡 IRE1α/JNK 信号通路发挥肾脏保护作用。
