美国宾夕法尼亚大学Katalin Susztak等研究人员合作发现，核受体ESRRA通过偶联新陈代谢和分化来预防肾脏疾病。该研究于2020年12月9日在线发表于国际一流学术期刊《细胞—代谢》。

研究人员使用单细胞RNA测序解析了受损的肾脏组织细胞组成上的差异，并在小鼠肾脏疾病模型中解析了细胞类型特异性基因表达。该分析突出显示了肾脏疾病中细胞多样性的重大变化，这显著影响了全肾脏转录组学的输出。细胞类型特异性差异表达分析确定近端小管（PT）细胞为关键的易损细胞类型。

通过无偏细胞轨迹分析，研究人员表明在肾脏疾病中PT细胞分化发生了改变。PT细胞中的代谢（脂肪酸氧化和氧化磷酸化）与PT细胞的分化和疾病呈现出最强且最可重复的关联。细胞分化和代谢的耦合是由核受体（雌激素相关受体α[ESRRA]和过氧化物酶体增殖激活受体α[PPARA]）建立的，它们可直接调控小鼠和患者样品中新陈代谢和PT细胞特异性基因的表达，并可在小鼠模型中预防肾脏疾病。

据了解，由于器官的细胞多样性，人们对肾脏疾病了解甚少。

附：英文原文

Title: The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation

Author: Poonam Dhillon, Jihwan Park, Carmen Hurtado del Pozo, Lingzhi Li, Tomohito Doke, Shizheng Huang, Juanjuan Zhao, Hyun Mi Kang, Rojesh Shrestra, Michael S. Balzer, Shatakshee Chatterjee, Patricia Prado, Seung Yub Han, Hongbo Liu, Xin Sheng, Pieterjan Dierickx, Kirill Batmanov, Juan P. Romero, Felipe Prósper, Mingyao Li, Liming Pei, Junhyong Kim, Nuria Montserrat, Katalin Susztak

Issue&Volume: 2020-12-09

Abstract: Kidney disease is poorly understood because of the organ’s cellular diversity. Weused single-cell RNA sequencing not only in resolving differences in injured kidneytissue cellular composition but also in cell-type-specific gene expression in mousemodels of kidney disease. This analysis highlighted major changes in cellular diversityin kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specificdifferential expression analysis identified proximal tubule (PT) cells as the keyvulnerable cell type. Through unbiased cell trajectory analyses, we show that PT celldifferentiation is altered in kidney disease. Metabolism (fatty acid oxidation andoxidative phosphorylation) in PT cells showed the strongest and most reproducibleassociation with PT cell differentiation and disease. Coupling of cell differentiationand the metabolism was established by nuclear receptors (estrogen-related receptoralpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) thatdirectly control metabolic and PT-cell-specific gene expression in mice and patientsamples while protecting from kidney disease in the mouse model.

DOI: 10.1016/j.cmet.2020.11.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30606-9