核受体 ESRRA 通过代谢和分化耦联保护肾脏疾病。
The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation.
机构信息
Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju, Republic of Korea.
出版信息
Cell Metab. 2021 Feb 2;33(2):379-394.e8. doi: 10.1016/j.cmet.2020.11.011. Epub 2020 Dec 9.
Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.
由于肾脏器官的细胞多样性，肾脏疾病的研究一直不够透彻。我们使用单细胞 RNA 测序技术，不仅可以解析肾脏损伤组织细胞组成的差异，还可以解析疾病小鼠模型中特定细胞类型的基因表达。该分析突出了肾脏疾病中细胞多样性的重大变化，这对整体肾脏转录组学结果产生了显著影响。细胞类型特异性差异表达分析确定近端肾小管 (PT) 细胞为关键易损细胞类型。通过无偏倚的细胞轨迹分析，我们发现肾脏疾病中 PT 细胞分化发生改变。PT 细胞中的代谢（脂肪酸氧化和氧化磷酸化）与 PT 细胞分化和疾病的相关性最强且最具重现性。核受体（雌激素相关受体 alpha [ESRRA] 和过氧化物酶体增殖物激活受体 alpha [PPARA]）将细胞分化和代谢联系起来，它们在小鼠和患者样本中直接控制代谢和 PT 细胞特异性基因表达，同时在小鼠模型中保护肾脏免受疾病影响。
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