PPARγ maintains the metabolic heterogeneity and homeostasis of renal tubules.
PPARγ maintains the metabolic heterogeneity and homeostasis of renal tubules.
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PPARgamma 维持肾小管的代谢异质性和稳态
DOI：
10.1016/j.ebiom.2018.10.072
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发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Zhou Q
中科院分区：
文献类型：
--
作者：
Lyu Z;Mao Z;Li Q;Xia Y;Liu Y;He Q;Wang Y;Zhao H;Lu Z;Zhou Q
肾小管在不同的节段中具有远距离的代谢特征和功能，每天重吸收约180 l水和25，000 mmol Na +中的>99%。肾小管中的代谢缺陷涉及肾脏疾病的病理生物学。然而，肾小管中代谢调节的潜在机制仍有待确定。采用串联质量标签（TMT）标记的定量质谱技术对C57 BL/6小鼠近端小管（PT）和远端小管（DT）的蛋白质组进行了定量比较。对差异表达蛋白进行生物信息学分析，发现PT和DT在代谢途径上存在显著差异。我们还进行了体外和体内试验，以研究PT和DT中远端代谢特征的分子机制。我们证明，肾近端小管（PT）具有高表达的脂质代谢酶，其被大量表达的PPARα/γ转录上调。相反，肾远端小管（DT）具有升高的糖酵解酶表达，这是由高表达的c-Myc介导的。重要的是，PPARγ在转录上增强PT中蛋白酶iRhom 2的表达，其抑制EGF的表达和分泌以及随后的EGFR依赖性糖酵解基因的表达和糖酵解。在小鼠PT中，PPARγ抑制降低iRhom 2表达并增加EGF和GLUT 1表达，导致肾小管肥大、肾小管间质纤维化和肾功能受损，2-脱氧-d-葡萄糖治疗可挽救这些症状。这些发现描绘了PT中活性脂质代谢和抑制糖酵解以及DT中活性糖酵解的潜在机制，并揭示了PPARs和c-Myc在维持肾脏代谢稳态中的关键作用。基金：本工作得到国家自然科学基金（赠款和81873932;给Q.Z.）的资助，重庆市科学技术委员会应用发展计划（cstc 2014 yykfB 10003; Q.Z.），重庆市科学技术委员会大众创意工作坊项目，重庆市科学技术委员会技术创新与应用专项示范项目（cstc 2018 jscx-mszdX 0022）。
The renal tubules, which have distant metabolic features and functions in different segments, reabsorb >99% of approximately 180 l of water and 25,000 mmol of Na + daily. Defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined. We quantitatively compared the proteomes of the isolated proximal tubules (PT) and distal tubules (DT) from C57BL/6 mouse using tandem mass tag (TMT) labeling-based quantitative mass spectrometry. Bioinformatics analysis of the differentially expressed proteins revealed the significant differences between PT and DT in metabolism pathway. We also performed in vitro and in vivo assays to investigate the molecular mechanism underlying the distant metabolic features in PT and DT. We demonstrate that the renal proximal tubule (PT) has high expression of lipid metabolism enzymes, which is transcriptionally upregulated by abundantly expressed PPARα/γ. In contrast, the renal distal tubule (DT) has elevated glycolytic enzyme expression, which is mediated by highly expressed c-Myc. Importantly, PPARγ transcriptionally enhances the protease iRhom2 expression in PT, which suppresses EGF expression and secretion and subsequent EGFR-dependent glycolytic gene expression and glycolysis. PPARγ inhibition reduces iRhom2 expression and increases EGF and GLUT1 expression in PT in mice, resulting in renal tubule hypertrophy, tubulointerstitial fibrosis and damaged kidney functions, which are rescued by 2-deoxy-d-glucose treatment. These findings delineate instrumental mechanisms underlying the active lipid metabolism and suppressed glycolysis in PT and active glycolysis in DT and reveal critical roles for PPARs and c-Myc in maintaining renal metabolic homeostasis. FUND: This work was supported by the National Natural Science Foundation of China (grants 81572076 and 81873932; to Q.Z.), the Applied Development Program of the Science and Technology Committee of Chongqing (cstc2014yykfB10003; Q.Z.), the Program of Populace Creativities Workshops of the Science and Technology Committee of Chongqing (Q.Z.), the special demonstration programs for innovation and application of techniques (cstc2018jscx-mszdX0022) from the Science and Technology Committee of Chongqing (Q.Z.).
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影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
13.6
作者：
Amsellem, Sabine;Gburek, Jakub;Kozyraki, Renata
通讯作者：
Kozyraki, Renata
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
13.6
作者：
Birn, H;Spiegelstein, O;Finnell, RH
通讯作者：
Finnell, RH
DOI：
10.1002/dvdy.22640
发表时间：
2011-06
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Georgas KM;Chiu HS;Lesieur E;Rumballe BA;Little MH
通讯作者：
Little MH