Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy
Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy
复制标题
二硫键氧化还原酶样蛋白可防止糖尿病肾病的异位脂肪沉积和脂质相关的肾脏损伤
DOI：
10.1016/j.kint.2018.10.038
复制
发表时间：
2019-04-01
影响因子：
19.6
通讯作者：
Sun, Lin
中科院分区：
文献类型：
--
作者：
Chen, Xianghui;Han, Yachun;Sun, Lin
肾脏异位脂肪沉积(EFD)已被证明在糖尿病肾病中起致病作用；然而，EFD的机制仍不清楚。通过转录组分析，我们发现高脂饮食加链脲佐菌素诱导的糖尿病小鼠肾脏中二硫键A氧化还原酶样蛋白(DsbA-L)的表达水平低于对照组小鼠。糖尿病小鼠脂肪细胞分化相关蛋白表达增加，I型胶原、纤维连接蛋白和磷酸化5 0AMP激活的激酶(p-AMPK)、脂肪甘油三酯脂肪酶(p-ATGL)和HMG-CoA还原酶(p-HMGCR)水平异常。这些改变伴随着肾脏中脂滴的沉积，并且在糖尿病DsbA-L基因敲除小鼠中更加明显。在体外，过表达DsbA-L可减轻高糖诱导的人近端肾小管上皮细胞内脂滴沉积，而DsbA-L siRNA可加重脂滴沉积，降低p-AMPK、p-ATGL和p-HMGCR水平。高糖和棕榈酸处理可增强IL-1β和IL-18的表达；经DsbA-L siRNA处理后，这些增强作用进一步增强，但与AMPK激活剂共同处理后，这些增强作用减弱。在糖尿病肾病患者的肾活检组织中，DsbA-L的表达与肾小管损害和肾小管功能障碍呈负相关。综上所述，这些结果表明，丹参-L对糖尿病肾病中的EFD和脂质相关的肾脏损害具有保护作用。AMPK通路的激活是DsbA-L肾脏作用的一个潜在机制。
Ectopic fat deposition (EFD) in the kidney has been shown to play a causal role in diabetic nephropathy; however, the mechanism underlying EFD remains elusive. By transcriptome analysis, we found decreased expression levels of disulfide-bond A oxidoreductase-like protein (DsbA-L) in the kidneys of diabetic mice (induced by high-fat diet plus Streptozotocin) compared with control mice. Increased expression of adipocyte differentiation-related protein and abnormal levels of collagen I, fibronectin, and phosphorylated 5 0 AMP-activated kinase (p-AMPK), adipose triglyceride lipase (p-ATGL), and HMG-CoA reductase (p-HMGCR) were also observed in diabetic mice. These alterations were accompanied by deposition of lipid droplets in the kidney, and were more pronounced in diabetic DsbA-L knockout mice. In vitro, overexpression of DsbA-L ameliorated high glucose-induced intracellular lipid droplet deposition in a human proximal tubular cell line, and DsbA-L siRNA aggravated lipid droplet deposition and reduced the levels of p-AMPK, p-ATGL, and p-HMGCR. High glucose and palmitic acid treatment enhanced the expression of interleukin-1 beta and interleukin-18; these enhancements were further increased after treatment with DsbA-L siRNA but alleviated by co-treatment with an AMPK activator. In kidney biopsy tissue from patients with diabetic nephropathy, DsbA-L expression was negatively correlated with EFD and tubular damage. Collectively, these results suggest that DsbA-L has a protective role against EFD and lipid-related kidney damage in diabetic nephropathy. Activation of the AMPK pathway is a potential mechanism underlying DsbA-L action in the kidney.