GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway

Lu, Jian; Chen, Pei Pei; Zhang, Jia Xiu; Li, Xue Qi; Wang, Gui Hua; Yuan, Ben Yin; Huang, Si Jia; Liu, Xiao Qi; Jiang, Ting Ting; Wang, Meng Ying; Liu, Wen Tao; Ruan, Xiong Zhong; Liu, Bi Cheng; Ma, Kun Ling

doi:10.7150/ijbs.64665

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Int J Biol Sci 2022; 18(1):96-111. doi:10.7150/ijbs.64665 This issue Cite

Research Paper

GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway

Jian Lu¹, Pei Pei Chen¹, Jia Xiu Zhang¹, Xue Qi Li¹, Gui Hua Wang¹, Ben Yin Yuan¹, Si Jia Huang¹, Xiao Qi Liu¹, Ting Ting Jiang¹, Meng Ying Wang¹, Wen Tao Liu¹, Xiong Zhong Ruan², Bi Cheng Liu¹, Kun Ling Ma^1✉

1. Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
2. John Moorhead Research Laboratory, Department of Renal Medicine, University College London (UCL) Medical School, Royal Free Campus, London, NW3 2PF, UK.

Citation:

Lu J, Chen PP, Zhang JX, Li XQ, Wang GH, Yuan BY, Huang SJ, Liu XQ, Jiang TT, Wang MY, Liu WT, Ruan XZ, Liu BC, Ma KL. GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. Int J Biol Sci 2022; 18(1):96-111. doi:10.7150/ijbs.64665. https://www.ijbs.com/v18p0096.htm

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Abstract

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms.

Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting.

Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results.

Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.

Keywords: diabetic nephropathy, podocytes, lipotoxicity, GPR43, autophagy, low-density lipoprotein receptor

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APA

Lu, J., Chen, P.P., Zhang, J.X., Li, X.Q., Wang, G.H., Yuan, B.Y., Huang, S.J., Liu, X.Q., Jiang, T.T., Wang, M.Y., Liu, W.T., Ruan, X.Z., Liu, B.C., Ma, K.L. (2022). GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. International Journal of Biological Sciences, 18(1), 96-111. https://doi.org/10.7150/ijbs.64665.

ACS

Lu, J.; Chen, P.P.; Zhang, J.X.; Li, X.Q.; Wang, G.H.; Yuan, B.Y.; Huang, S.J.; Liu, X.Q.; Jiang, T.T.; Wang, M.Y.; Liu, W.T.; Ruan, X.Z.; Liu, B.C.; Ma, K.L. GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. Int. J. Biol. Sci. 2022, 18 (1), 96-111. DOI: 10.7150/ijbs.64665.

NLM

CSE

Lu J, Chen PP, Zhang JX, Li XQ, Wang GH, Yuan BY, Huang SJ, Liu XQ, Jiang TT, Wang MY, Liu WT, Ruan XZ, Liu BC, Ma KL. 2022. GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. Int J Biol Sci. 18(1):96-111.

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