Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.
Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.
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纤维化是导致慢性和终末期肾病的进行性通常不可逆过程的组织学表现。对正常和纤维化人肾小管样品的大队列（n=95）的全基因组转录组研究，随后进行系统和网络分析，将炎症和代谢确定为患病肾脏中的最高失调途径。特别是，我们发现人类和小鼠模型肾小管间质纤维化的关键酶和脂肪酸氧化（FAO）的调节剂的表达较低，细胞内脂质沉积增加。体外实验表明，抑制肾小管上皮细胞中的脂肪酸氧化导致ATP耗竭、细胞死亡、去分化和细胞内脂质沉积;这是在纤维化中观察到的一种表型。通过遗传或药理学方法恢复脂肪酸代谢保护小鼠免受肾小管间质纤维化。我们的研究结果提出了纠正代谢缺陷可能有助于预防和治疗慢性肾脏疾病的可能性。
Fibrosis is the histological manifestation of a progressive usually irreversible process causing chronic and end stage kidney disease. Genome-wide transcriptome studies of a large cohort (n=95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses identified inflammation and metabolism as top dysregulated pathways in diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and increased intracellular lipid deposition. In vitro experiments indicated that inhibition of fatty acid oxidation in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition; a phenotype observed in fibrosis. Restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect may be useful for preventing and treating chronic kidney disease.
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DOI：
10.1152/ajpendo.1997.273.3.e650
发表时间：
1997-09-01
影响因子：
5.1
作者：
Meyer, C;Nadkarni, V;Gerich, J
通讯作者：
Gerich, J
影响因子：
15.9
作者：
Samudio, Ismael;Harmancey, Romain;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
82.9
作者：
Rowe I;Chiaravalli M;Mannella V;Ulisse V;Quilici G;Pema M;Song XW;Xu H;Mari S;Qian F;Pei Y;Musco G;Boletta A
通讯作者：
Boletta A
影响因子：
13.2
作者：
Ansquer, JC;Foucher, C;Steiner, G
通讯作者：
Steiner, G
影响因子：
13.6
作者：
Kovesdy, Csaba P.;Anderson, John E.;Kalantar-Zadeh, Kamyar
通讯作者：
Kalantar-Zadeh, Kamyar