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. 2022 Dec 15;311(Pt A):121142.
doi: 10.1016/j.lfs.2022.121142. Epub 2022 Oct 29.

NAG-1/GDF15 inhibits diabetic nephropathy via inhibiting AGE/RAGE-mediated inflammation signaling pathways in C57BL/6 mice and HK-2 cells

Jiajun Chen  1 , He Peng  1 , Chaojie Chen  1 , Ying Wang  1 , Tingting Sang  1 , Zheqi Cai  2 , Qian Zhao  1 , Shengjia Chen  1 , Xiaojian Lin  1 , Thomas Eling  3 , Xingya Wang  4
Affiliations

NAG-1/GDF15 inhibits diabetic nephropathy via inhibiting AGE/RAGE-mediated inflammation signaling pathways in C57BL/6 mice and HK-2 cells

Jiajun Chen et al. Life Sci. .

Abstract

Aims: 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.

Main methods: 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.

Key findings: 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.

Significance: NAG-1/GDF15 plays an important role in the inhibition of the development and progression of DN via targeting AGE/RAGE-mediated inflammation pathways.

Keywords: AGE/RAGE; Diabetic nephropathy; Hyperglycemia; Inflammation; NAG-1/GDF15; TLR4/MyD88/NF-κB.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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