Wang Xiao-Hua, Ao Qiang-Guo, Cheng Qing-Li
Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China.
Ann Transl Med. 2021 Jun;9(12):979. doi: 10.21037/atm-21-2218.
The renal artery plays a central role in renal perfusion and is critical for proper renal function. Ageing is an independent risk factor for both impaired renal function and vascular disorders, and associated with an increase in the expression of the vasoconstrictor endothelin-1 (ET-1), and caloric restriction (CR) without malnutrition has been shown to be an effective inhibitor of renal dysfunction induced by ageing. The objective of this study was to determine whether CR-mediated alleviation of renal dysfunction is mediated by ET-1 expression.
The young (2 months, 2 M) and old (12 months, 12 M) Sprague-Dawley male rats were used and fed ad libitum. The 12-month-old rats were further divided into 12 M and 12 M-caloric restriction (CR) (30% calorie restriction). After 8 weeks, the renal tissues were showed by PAS staining, and age-related metabolic parameters and renal functions were detected in each group of rats. The inflammatory cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) were analyzed using ELISA. The mRNA and protein expression in the renal artery were analysis by qRT-PCR and Immunoblot analysis.
Ageing was associated with significant increases in 24 h urine protein content and serum triglyceride and cholesterol in 12 M rats, both of which were significantly inhibited in 12 M-CR. The mRNA expression and the secretion of IL-6, IL-1β, TNF-α, and TGF-β1 in the renal artery was significantly increased with ageing and inhibited by CR. CR also inhibited ageing-induced (encoding ET-1) mRNA and protein expression in the renal artery. In addition, CR could regulate ET-1 expression by inhibiting the activation of NF-κB signaling and activation and induction in the expression of NF-E2-related factor 2 (Nrf2) and histone deacetylase and gene repressor sirtuin 1 (SIRT1), both of which play a central role in mitigating oxidative stress in young rats.
Moderate CR can reverse the ageing related kidney dysfunction by reducing the ET-1 expression. CR might be used as an alternative to prevent the ageing induced renal artery dysfunction.
肾动脉在肾脏灌注中起核心作用，对肾脏正常功能至关重要。衰老既是肾功能受损的独立危险因素，也是血管疾病的独立危险因素，且与血管收缩因子内皮素 -1（ET-1）表达增加有关，而无营养不良的热量限制（CR）已被证明是衰老诱导的肾功能障碍的有效抑制剂。本研究的目的是确定CR介导的肾功能障碍缓解是否由ET-1表达介导。
使用年轻（2个月，2M）和老年（12个月，12M）的Sprague-Dawley雄性大鼠，并随意喂食。将12个月大的大鼠进一步分为12M组和12M热量限制（CR）组（30%热量限制）。8周后，通过PAS染色观察肾组织，并检测每组大鼠与年龄相关的代谢参数和肾功能。使用酶联免疫吸附测定法（ELISA）分析白细胞介素（IL）-6、IL-1β、肿瘤坏死因子α（TNF-α）和转化生长因子β1（TGF-β1）的炎性细胞因子。通过实时定量聚合酶链反应（qRT-PCR）和免疫印迹分析来分析肾动脉中的mRNA和蛋白质表达。
衰老与12M大鼠24小时尿蛋白含量、血清甘油三酯和胆固醇的显著增加有关，而这两者在12M-CR组中均受到显著抑制。随着衰老，肾动脉中IL-6、IL-1β、TNF-α和TGF-β1的mRNA表达和分泌显著增加，并被CR抑制。CR还抑制衰老诱导的（编码ET-1）肾动脉中的mRNA和蛋白质表达。此外，CR可通过抑制核因子κB（NF-κB）信号通路的激活以及NF-E2相关因子2（Nrf2）和组蛋白去乙酰化酶及基因抑制因子沉默调节蛋白1（SIRT1）表达的激活和诱导来调节ET-1表达，这两者在减轻年轻大鼠氧化应激中起核心作用。
适度的CR可通过降低ET-1表达来逆转与衰老相关的肾功能障碍。CR可能用作预防衰老诱导的肾动脉功能障碍的替代方法。
