（Pro）肾素受体导致糖尿病小鼠肾线粒体功能障碍，细胞凋亡和纤维化。,Scientific Reports

当前位置： X-MOL 学术 › Sci. Rep. › 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.)

（Pro）肾素受体导致糖尿病小鼠肾线粒体功能障碍，细胞凋亡和纤维化。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-08-12 , DOI: 10.1038/s41598-019-47055-1
Caixia Li ₁ , Luis C Matavelli ₁ , Safia Akhtar ₁ , Helmy M Siragy ₁

Affiliation

最近，我们证明了糖尿病患者中肾脏（Pro）肾素受体（PRR）表达的增加有助于糖尿病性肾脏疾病的发展。但是，涉及PRR活性和糖尿病性肾功能不全的确切机制尚不清楚。我们假设PRR位于肾脏线粒体中，并通过氧化应激诱导的线粒体功能障碍促进肾脏纤维化和细胞凋亡。对照和链脲佐菌素诱导的糖尿病C57BL / 6小鼠被注射scramble shRNA和PRR shRNA，随后进行八周。在研究结束时，糖尿病小鼠在总肾脏组织和肾脏线粒体部分均显示PRR和NOX4的表达增加。此外，糖尿病小鼠的肾脏线粒体蛋白表达降低，SOD2和ATP生成活性降低，UCP2表达升高。在糖尿病肾中，caspase3，phos-Foxo3a，phos-NF-κB，纤连蛋白和胶原蛋白IV的表达上调，而Sirt1和总FOXO3a的表达降低。肾脏免疫染色显示糖尿病肾中PRR，胶原蛋白和纤连蛋白的沉积增加。在糖尿病小鼠中，PRR抑制可降低尿白蛋白与肌酐的比率，并降低PRR，NOX4，UCP2，caspase3，phos-FOXO3a，phos-NF-κB，胶原蛋白和纤连蛋白的肾脏表达，同时增加肾线粒体的表达和SOD2的活性，ATP的产生以及Sirt1和total-FOXO3a的肾脏表达。总之，通过上调线粒体NOX4 / SOD2 / UCP2信号通路，在肾线粒体和糖尿病肾中PRR的表达增加会诱导线粒体功能障碍，并增强糖尿病肾脏的细胞凋亡和纤维化。

"点击查看英文标题和摘要"

(Pro)renin receptor contributes to renal mitochondria dysfunction, apoptosis and fibrosis in diabetic mice.

Recently we demonstrated that increased renal (Pro)renin receptor (PRR) expression in diabetes contributes to development of diabetic kidney disease. However, the exact mechanisms involving PRR activity and diabetic kidney dysfunction are unknown. We hypothesized that PRR is localized in renal mitochondria and contributes to renal fibrosis and apoptosis through oxidative stress-induced mitochondria dysfunction. Controls and streptozotocin-induced diabetic C57BL/6 mice were injected with scramble shRNA and PRR shRNA and followed for a period of eight weeks. At the end of study, diabetic mice showed increased expressions of PRR and NOX4 in both total kidney tissue and renal mitochondria fraction. In addition, renal mitochondria of diabetic mice showed reduced protein expression and activity of SOD2 and ATP production and increased UCP2 expression. In diabetic kidney, there was upregulation in the expressions of caspase3, phos-Foxo3a, phos-NF-κB, fibronectin, and collagen IV and reduced expressions of Sirt1 and total-FOXO3a. Renal immunostaining revealed increased deposition of PRR, collagen and fibronectin in diabetic kidney. In diabetic mice, PRR knockdown decreased urine albumin to creatinine ratio and the renal expressions of PRR, NOX4, UCP2, caspase3, phos-FOXO3a, phos-NF-κB, collagen, and fibronectin, while increased the renal mitochondria expression and activity of SOD2, ATP production, and the renal expressions of Sirt1 and total-FOXO3a. In conclusion, increased expression of PRR localized in renal mitochondria and diabetic kidney induced mitochondria dysfunction, and enhanced renal apoptosis and fibrosis in diabetes by upregulation of mitochondria NOX4/SOD2/UCP2 signaling pathway.

更新日期：2019-08-12

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南