Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 1TN, UK.
Nefrología y Metabolismo Mineral, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador CDMX 14080, Mexico.
Biomolecules. 2021 Jan 7;11(1):73. doi: 10.3390/biom11010073.
Renal injury observed in several pathologies has been associated with lipid accumulation in the kidney. While it has been suggested that the accumulation of renal lipids depends on free fatty acids released from adipose tissue, it is not known whether in situ renal lipogenesis due to endoplasmic reticulum (ER) stress contributes to kidney injury. The aim of the present study was to elucidate the role of pharmacological ER stress in renal structure and function and its effect on renal lipid metabolism of C57BL/6 mice. ER stress increased serum creatinine and induced kidney structural abnormalities. Tunicamycin-administered mice developed hyperinsulinemia, augmented lipolysis and increased circulating leptin and adiponectin. Renal unfolded protein response (UPR) gene expression markers, the lipogenic transcription factor SREBP1 and the phosphorylation of eIF2α increased 8 h after tunicamycin administration. At 24 h, an increase in BiP protein content was accompanied by a reduction in p-eIF2α and increased SREBP-1 and FASn protein content, in addition to a significant increase in triglyceride content and a reduction in AMPK. Thus, ER stress induces in situ lipid synthesis, leading to renal lipid accumulation and functional alterations. Future pharmacological and/or dietary strategies must target renal ER stress to prevent kidney damage and the progression of metabolic diseases.
在几种病理学中观察到的肾损伤与肾脏脂质积累有关。虽然有人提出肾脏脂质的积累取决于从脂肪组织释放的游离脂肪酸，但尚不清楚内质网 (ER) 应激引起的原位肾脂肪生成是否会导致肾脏损伤。本研究旨在阐明药理学 ER 应激在肾脏结构和功能中的作用及其对 C57BL/6 小鼠肾脏脂质代谢的影响。ER 应激增加了血清肌酐并诱导了肾脏结构异常。衣霉素给药的小鼠发生了高胰岛素血症，脂肪分解增加，循环瘦素和脂联素增加。内质网应激后 8 小时，肾脏未折叠蛋白反应 (UPR) 基因表达标志物、脂肪生成转录因子 SREBP1 和 eIF2α 的磷酸化增加。24 小时时，BiP 蛋白含量增加伴随着 p-eIF2α 的减少以及 SREBP-1 和 FASn 蛋白含量的增加，甘油三酯含量显著增加，AMPK 减少。因此，内质网应激诱导原位脂质合成，导致肾脏脂质积累和功能改变。未来的药理学和/或饮食策略必须针对肾脏内质网应激，以预防肾脏损伤和代谢性疾病的进展。
