School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311400, PR China.
College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, PR China.
Life Sci. 2022 Dec 15;311(Pt A):121142. doi: 10.1016/j.lfs.2022.121142. Epub 2022 Oct 29.
Our previous studies showed that the nonsteroidal anti-inflammatory drug-activated gene-1, or growth differentiation factor-15 (NAG-1/GDF15) inhibits obesity and diabetes in mice. The current study aimed to examine the role and molecular mechanisms of NAG-1/GDF15 in diabetic nephropathy (DN), which is largely unknown.
Both male and female wild-type (Wt) C57BL/6 mice and mice overexpressing human NAG-1/GDF15 (transgenic, Tg) were used, which were induced by high-fat diet (HFD)/streptozotocin (STZ) to establish the mouse model of DN. Transcriptome study was performed to identify the underlying molecular mechanisms of NAG-1/GDF15 against DN. In addition, human renal tubular epithelial cells (HK-2) were cultured with high glucose (HG) to establish a DN cellular model and were treated with NAG-1/GDF15 plasmid or the recombinant NAG-1/GDF15 protein for mechanism studies.
Overexpression of NAG-1/GDF15 in Tg mice significantly alleviated HFD/STZ-induced typical symptoms of DN, improved lipid homeostasis, glucose intolerance, and insulin sensitivity. Histopathology of renal tissues revealed that NAG-1/GDF15 mice had significantly reduced renal injury, glycogen deposition, and renal fibrosis. Transcriptome study uncovered inflammation, cell adhesion, and the inflammation-related signaling pathways as major pathways suppressed in the NAG-1/GDF15 mice. Further studies demonstrated that NAG-1/GDF15 overexpression inhibited renal and systematic inflammation, inhibited the AGE/RAGE axis and its associated downstream inflammatory molecules and adhesion molecules, and inhibited the upregulation of TLR4/MyD88/NF-κB signaling pathway in mice. These results were further confirmed in HG-induced HK-2 cells.
NAG-1/GDF15 plays an important role in the inhibition of the development and progression of DN via targeting AGE/RAGE-mediated inflammation pathways.
我们之前的研究表明，非甾体抗炎药激活基因 1（或生长分化因子 15，NAG-1/GDF15）可抑制肥胖和糖尿病小鼠的发病。本研究旨在探讨 NAG-1/GDF15 在糖尿病肾病（DN）中的作用及其分子机制，目前这方面的研究尚不清楚。
使用雄性和雌性野生型（Wt）C57BL/6 小鼠和过表达人 NAG-1/GDF15（转基因，Tg）的小鼠，通过高脂肪饮食（HFD）/链脲佐菌素（STZ）诱导建立 DN 小鼠模型。进行转录组研究以确定 NAG-1/GDF15 对 DN 的潜在分子机制。此外，用高糖（HG）培养人肾小管上皮细胞（HK-2）建立 DN 细胞模型，并使用 NAG-1/GDF15 质粒或重组 NAG-1/GDF15 蛋白进行机制研究。
Tg 小鼠中 NAG-1/GDF15 的过表达显著缓解了 HFD/STZ 诱导的 DN 的典型症状，改善了脂代谢平衡、葡萄糖耐量和胰岛素敏感性。肾脏组织病理学显示，NAG-1/GDF15 小鼠的肾脏损伤、糖原沉积和肾纤维化明显减少。转录组研究揭示了炎症、细胞黏附和炎症相关信号通路是 NAG-1/GDF15 小鼠中受抑制的主要通路。进一步的研究表明，NAG-1/GDF15 的过表达抑制了肾脏和全身炎症，抑制了 AGE/RAGE 轴及其相关下游炎症分子和黏附分子的表达，并抑制了 TLR4/MyD88/NF-κB 信号通路的上调。这些结果在 HG 诱导的 HK-2 细胞中得到了进一步证实。
NAG-1/GDF15 通过靶向 AGE/RAGE 介导的炎症通路，在抑制 DN 的发生和发展方面发挥重要作用。
