Dysregulation of argininosuccinate synthase 1, phosphoenolpyruvate carboxykinase 1, and carbonyl reductase 3: Key arginine–proline metabolic mediators in mesangioproliferative glomerulopathies
Abstract
Aberrant proliferation of mesangial cells (MCs) is a central driver of glomerular injury in IgA nephropathy (IgAN) and lupus nephritis (LN), the two most common mesangioproliferative glomerulopathies. Emerging evidence implicates dysregulated arginine–proline metabolism in this process; however, the key regulatory genes and underlying mechanisms remain incompletely defined. Here, we performed integrative bulk RNA sequencing of glomerular datasets and applied machine learning algorithms (LASSO and SVM-RFE) to identify disease-specific differentially expressed genes (DEGs) linked to the arginine–proline metabolic pathway. We identified 34 LN-specific and 18 IgAN-specific DEGs, among which ASS1, PCK1, and CBR3 emerged as core hub genes through feature selection and network analyses. A nomogram-based diagnostic model incorporating these genes demonstrated strong predictive performance, with AUC values exceeding 0.75 in internal cohorts and robust validation across external datasets. Single-cell RNA sequencing of mouse models delineated seven MC subclusters, highlighting Rasl12+ and Col3a1+ subpopulations with pronounced proliferative–inflammatory phenotypes, characterized by downregulated ASS1 and PCK1 and upregulated CBR3. These transcriptional patterns were corroborated in vivo in anti-Thy1 nephritis rats, BAFF-transgenic IgAN mice, and MRL/lpr LN mice, where altered gene expression correlated with mesangial hyperplasia, macrophage infiltration, and elevated inflammatory cytokines. Functional assays in PDGF-BB–stimulated human MCs further demonstrated that overexpression of ASS1 or PCK1, or knockdown of CBR3, attenuated MC activation, proliferation, and proinflammatory crosstalk with macrophages. Collectively, our results position ASS1, PCK1, and CBR3 as pivotal regulators of arginine-proline metabolism in mesangial proliferation, establishing them as innovative diagnostic biomarkers and therapeutic targets for precise management of IgAN and LN.
Document Type
Journal Article
Date of Publication
1-1-2026
Volume
337
PubMed ID
41352509
Publication Title
International Journal of Biological Macromolecules
Publisher
Elsevier
School
School of Medical and Health Sciences
Funders
China Postdoctoral Science Foundation (GZB20240415) / Australia-China International Collaborative Grant (NSFC 81561128020) / Western Australian Future Health Research and Innovation Fund (WANMA/EL2023-24/2, WANMA/Ideas2024-25/5) / Beijing Tsinghua Changgung Hospital Fund (12024C01002) / Medical Scientific Research Foundation of Guangdong Province (B2025748)
Grant Number
NHMRC Number : APP1112767
Copyright
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Comments
He, J., Peng, F., Qu, Y., Zhao, Y., Li, Y., Zhou, Y., Guo, C., Li, X., Song, M., Chen, X., Hong, Q., & Wang, W. (2025). Dysregulation of argininosuccinate synthase 1, phosphoenolpyruvate carboxykinase 1, and carbonyl reductase 3: Key arginine–proline metabolic mediators in mesangioproliferative glomerulopathies. International Journal of Biological Macromolecules, 337(part 2), 149479. https://doi.org/10.1016/j.ijbiomac.2025.149479