UCP2-induced hypoxia promotes lipid accumulation and tubulointerstitial fibrosis during ischemic kidney injury.,Cell Death & Disease

当前位置： X-MOL 学术 › Cell Death Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

UCP2-induced hypoxia promotes lipid accumulation and tubulointerstitial fibrosis during ischemic kidney injury.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41419-019-2219-4
Qingqing Ke ₁ , Qi Yuan ₁ , Nan Qin ₁ , Caifeng Shi ₁ , Jing Luo ₁ , Yi Fang ₁ , Lingling Xu ₁ , Qi Sun ₁ , Ke Zen ₂ , Lei Jiang ₁ , Yang Zhou ₁ , Junwei Yang ₁

Affiliation

Mitochondrial dysfunction leads to loss of renal function and structure; however, the precise mechanisms by which mitochondrial function can regulate renal fibrosis remain unclear. Proximal tubular cells (PTCs) prefer fatty acid oxidation as their energy source and dysregulation of lipid metabolism has been linked to tubulointerstitial fibrosis (TIF). Here, we demonstrated that mitochondrial uncoupling protein 2 (UCP2) regulates TIF through the stimulation of lipid deposition and extracellular matrix (ECM) accumulation. We show that UCP2 expression was increased in human biopsy sample and mouse kidney tissues with TIF. Moreover, UCP2-deficient mice displayed mitigated renal fibrosis in I/R-induced mouse model of TIF. Consistent with these results, UCP2 deficiency displayed reduced lipid deposition and ECM accumulation in vivo and in vitro. In UCP2-deficient PTCs, inhibition of TIF resulted from downregulation of hypoxia-inducible factor-1α (HIF-1α), a key regulator of lipid metabolism and ECM accumulation. Furthermore, we describe a molecular mechanism by which UCP2 regulates HIF-1α stabilization through regulation of mitochondrial respiration and tissue hypoxia during TIF. HIF-1α inhibition by siRNA suppressed lipid and ECM accumulation by restoration of PPARα and CPT1α, as well as suppression of fibronectin and collagen I expression in PTCs. In conclusion, our results suggest that UCP2 regulates TIF by inducing the HIF-1α stabilization pathway in tubular cells. These results identify UCP2 as a potential therapeutic target in treating chronic renal fibrosis.

中文翻译：

在缺血性肾损伤期间，UCP2诱导的缺氧促进脂质积累和肾小管间质纤维化。

线粒体功能障碍导致肾功能和结构丧失；然而，线粒体功能调节肾纤维化的确切机制仍不清楚。近端肾小管细胞（PTC）更喜欢脂肪酸氧化作为其能量来源，脂质代谢失调与肾小管间质纤维化（TIF）有关。在这里，我们证明了线粒体解偶联蛋白2（UCP2）通过刺激脂质沉积和细胞外基质（ECM）积累来调节TIF。我们显示，UCP2表达在人类活检样本和TIF小鼠肾脏组织中增加。此外，UCP2缺陷小鼠在I / R诱导的TIF小鼠模型中显示出减轻的肾纤维化。与这些结果一致，UCP2缺乏症显示体内和体外脂质沉积和ECM积累减少。在UCP2缺陷型PTC中，TIF的抑制是由缺氧诱导因子-1α（HIF-1α）的下调引起的，该因子是脂质代谢和ECM积累的关键调节因子。此外，我们描述了一种分子机制，通过该分子机制，UCP2通过调节TIF期间的线粒体呼吸和组织缺氧来调节HIF-1α的稳定性。siRNA抑制HIF-1α通过恢复PPARα和CPT1α抑制脂质和ECM积累，并抑制PTC中纤连蛋白和胶原I的表达。总之，我们的结果表明，UCP2通过诱导小管细胞中的HIF-1α稳定途径来调节TIF。这些结果确定了UCP2是治疗慢性肾纤维化的潜在治疗靶标。脂质代谢和ECM积累的关键调节剂。此外，我们描述了一种分子机制，通过该分子机制，UCP2通过调节TIF期间的线粒体呼吸和组织缺氧来调节HIF-1α的稳定性。siRNA抑制HIF-1α通过恢复PPARα和CPT1α抑制脂质和ECM积累，并抑制PTC中纤连蛋白和胶原I的表达。总之，我们的结果表明，UCP2通过诱导小管细胞中的HIF-1α稳定途径来调节TIF。这些结果确定了UCP2是治疗慢性肾纤维化的潜在治疗靶标。脂质代谢和ECM积累的关键调节剂。此外，我们描述了一种分子机制，通过该分子机制，UCP2通过调节TIF期间的线粒体呼吸和组织缺氧来调节HIF-1α的稳定性。siRNA抑制HIF-1α通过恢复PPARα和CPT1α抑制脂质和ECM积累，并抑制PTC中纤连蛋白和胶原I的表达。总之，我们的结果表明，UCP2通过诱导小管细胞中的HIF-1α稳定途径来调节TIF。这些结果确定了UCP2是治疗慢性肾纤维化的潜在治疗靶标。siRNA抑制HIF-1α通过恢复PPARα和CPT1α抑制脂质和ECM积累，并抑制PTC中纤连蛋白和胶原I的表达。总之，我们的结果表明，UCP2通过诱导小管细胞中的HIF-1α稳定途径来调节TIF。这些结果确定了UCP2是治疗慢性肾纤维化的潜在治疗靶标。siRNA抑制HIF-1α通过恢复PPARα和CPT1α抑制脂质和ECM积累，并抑制PTC中纤连蛋白和胶原I的表达。总之，我们的结果表明，UCP2通过诱导小管细胞中的HIF-1α稳定途径来调节TIF。这些结果确定了UCP2是治疗慢性肾纤维化的潜在治疗靶标。

更新日期：2020-01-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11