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Original Article Basic Research Ras Guanine Nucleotide-Releasing Protein-4 Inhibits Erythropoietin Production in Diabetic Mice with Kidney Disease by Degrading HIF2A
Junmei Wang1,2,*orcid , Shuai Huang1,2,3,*orcid , Li Zhang1,2,*orcid , Yixian He1,2, Xian Shao1,2, A-Shan-Jiang A-Ni-Wan1,2, Yan Kong1,2, Xuying Meng1,2, Pei Yu1,2orcid , Saijun Zhou1,2orcid

DOI: https://doi.org/10.4093/dmj.2024.0398 [Epub ahead of print]
Published online: January 23, 2025
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1NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
2Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China
3Department of Geriatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
Corresponding author:  Pei Yu,
Email: yupei@tmu.edu.cn
Saijun Zhou,
Email: zhousaijun@tmu.edu.cn
*These authors contributed equally to this work.
Received: 18 July 2024   • Accepted: 7 September 2024

Background
In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes.
Methods
The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments.
Results
RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice.
Conclusion
RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

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Wang J, Huang S, Zhang L, He Y, Shao X, A-Ni-Wan ASJ, Kong Y, Meng X, Yu P, Zhou S. Ras Guanine Nucleotide-Releasing Protein-4 Inhibits Erythropoietin Production in Diabetic Mice with Kidney Disease by Degrading HIF2A. Diabetes Metab J. 2025 Jan 23. doi: 10.4093/dmj.2024.0398. Epub ahead of print.
Received: Jul 18, 2024; Accepted: Sep 07, 2024
DOI: https://doi.org/10.4093/dmj.2024.0398.

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