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

Jiajun Chen; He Peng; Chaojie Chen; Ying Wang; Tingting Sang; Zheqi Cai; Qian Zhao; Shengjia Chen; Xiaojian Lin; Thomas Eling; Xingya Wang

doi:10.1016/j.lfs.2022.121142

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

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

Authors

Affiliations

¹ School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311400, PR China.
² College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, PR China.
³ Scientist Emeritus, National Institute of Environmental Health Science, Research Triangle Park, NC, 27709, USA.
⁴ School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311400, PR China. Electronic address: xywang@zcmu.edu.cn.

PMID: 36367498
DOI: 10.1016/j.lfs.2022.121142

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.

MeSH terms

Animals
Diabetes Mellitus, Experimental* / metabolism
Diabetic Nephropathies* / metabolism
Female
Glycation End Products, Advanced / metabolism
Growth Differentiation Factor 15 / genetics
Humans
Inflammation / pathology
Male
Mice
Mice, Inbred C57BL
Receptor for Advanced Glycation End Products / metabolism
Signal Transduction
Streptozocin / pharmacology

Substances

GDF15 protein, human
Growth Differentiation Factor 15
Streptozocin
Receptor for Advanced Glycation End Products
Glycation End Products, Advanced