PDF(Pubmed)
Abstract：
Oxalate-induced damage to renal tubular epithelial cells (RTECs) is an essential factor in the incident kidney stone, but the specific mechanism is unclear. Recent research has pinpointed interacting areas within the endoplasmic reticulum and mitochondria, called mitochondria-associated membranes (MAMs). These studies have linked endoplasmic reticulum stress (ERS) and oxidative imbalance to kidney disease development. The sigma-1 receptor (S1R), a specific protein found in MAMs, is involved in various physiological processes, but its role in oxalate-induced kidney stone formation remains unclear. In this study, we established cellular and rat models of oxalate-induced kidney stone formation to elucidate the S1R\'s effects against ERS and apoptosis and its mechanism in oxalate-induced RTEC injury. We found that oxalate downregulated S1R expression in RTECs and escalated oxidative stress and ERS, culminating in increased apoptosis. The S1R agonist dimemorfan up-regulated S1R expression and mitigated ERS and oxidative stress, thereby reducing apoptosis. This protective effect was mediated through S1R inhibition of the CHOP pathway. Animal experiments demonstrated that S1R\'s activation attenuated oxalate-induced kidney injury and alleviated kidney stone formation. This is the first study to establish the connection between S1R and kidney stones, suggesting S1R\'s protective role in inhibiting ERS-mediated apoptosis to ameliorate kidney stone formation.
摘要：
草酸盐对肾小管上皮细胞（RTEC）的损害是肾结石事件的重要因素。但具体机制尚不清楚。最近的研究已经确定了内质网和线粒体内的相互作用区域，称为线粒体相关膜（MAMs）。这些研究将内质网应激（ERS）和氧化失衡与肾脏疾病的发展联系起来。sigma-1受体(S1R),在MAMs中发现的一种特定蛋白质，参与各种生理过程，但其在草酸盐诱导的肾结石形成中的作用尚不清楚。在这项研究中,我们建立了草酸盐诱导的肾结石形成的细胞和大鼠模型，以阐明S1R对ERS和细胞凋亡的影响及其在草酸盐诱导的RTEC损伤中的机制。我们发现草酸盐下调RTEC中S1R的表达，并加剧氧化应激和ERS，最终导致细胞凋亡增加。S1R激动剂二记忆体上调S1R表达，减轻ERS和氧化应激，从而减少细胞凋亡。这种保护作用是通过S1R抑制CHOP途径介导的。动物实验表明，S1R的激活减轻了草酸盐引起的肾损伤，减轻了肾结石的形成。这是第一个建立S1R与肾结石之间联系的研究，提示S1R在抑制ERS介导的细胞凋亡以改善肾结石形成中的保护作用。
