Tubular Mas receptor mediates lipid-induced kidney injury.
Tubular Mas receptor mediates lipid-induced kidney injury.
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管状Mas受体介导脂质诱导的肾损伤
DOI：
10.1038/s41419-020-03375-z
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发表时间：
2021-01-21
影响因子：
9
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Kong Y;Zhao X;Qiu M;Lin Y;Feng P;Li S;Liang B;Zhu Q;Huang H;Li C;Wang W
肥胖相关的肾脏疾病正在成为世界范围内严重的健康问题，但肥胖导致肾损伤的机制尚未完全了解。本研究旨在探讨Mas受体在脂质性肾损伤中的作用。在喂食高脂饮食（HFD）的小鼠中，自噬、内质网应激（ER应激）和细胞凋亡标志物的蛋白丰度在肾皮质中显著增加，Mas缺失（Mas-/-）或Mas受体拮抗剂A779显著阻止了这一点。棕榈酸（PA）诱导持续增加的自噬，ER应激，凋亡以及原代培养的近端肾小管细胞的野生型，但不是从Mas−/−小鼠的线粒体损伤。在人近端肾小管HK 2细胞中，Mas激动剂Ang（1-7）或AVE 0991可加重PA诱导的自噬和ER应激，但A779或Mas敲低可减弱PA诱导的自噬和ER应激。在PA处理的HK 2细胞中，激活Mas导致细胞内[Ca 2 +] i升高，而抑制或敲低Mas则降低[Ca 2 +]i。线粒体外膜电压依赖性阴离子通道（VDAC 1）在PA处理的HK 2细胞中显著上调，这与受损的线粒体形态和去极化有关。AVE 0991可增强这些效应，A779或Mas敲低可抑制这些效应。在HK 2细胞中，Mas敲低阻止了由PA诱导的VDAC 1、自噬衔接子P62和泛素之间的相互作用受损，导致VDAC 1潜在的泛素化。总之，Mas受体介导的脂质诱导肾脏自噬和ER应激受损，可能导致肥胖相关肾脏疾病中的肾小管损伤。
Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas−/−) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas−/−mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1–7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca2+]iin HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca2+]i. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.
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DOI：
10.1152/ajprenal.00401.2012
发表时间：
2013-05-01
影响因子：
4.2
作者：
Castelo-Branco, Regiane C.;Leite-Delova, Deise C. A.;de Mello-Aires, Margarida
通讯作者：
de Mello-Aires, Margarida
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影响因子：
7.2
作者：
Chen, Haibo;Gao, Weiwei;Tian, Ye
通讯作者：
Tian, Ye
DOI：
10.1152/ajprenal.00426.2009
发表时间：
2010-06-01
影响因子：
4.2
作者：
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通讯作者：
Burns, Kevin D.
影响因子：
19.6
作者：
Pinheiro, Sergio V. B.;Ferreira, Anderson J.;Simoes e Silva, Ana Cristina
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DOI：
10.1152/ajprenal.00557.2016
发表时间：
2017-08-01
影响因子：
4.2
作者：
Castelo-Branco, Regiane Cardoso;Leite-Dellova, Deise C. A.;de Mello-Aires, Margarida
通讯作者：
de Mello-Aires, Margarida