Glycine Decarboxylase Advances IgA nephropathy by Boosting Mesangial Cell Proliferation through the Pyrimidine Pathway

 

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Glycine Decarboxylase Advances IgA nephropathy by Boosting Mesangial Cell Proliferation through the Pyrimidine Pathway

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Yi
Xiong
Yi Xiong xy17231106@163.com The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Department of Nephrology Nanchang China *
Honghong Zou ndefy21195@ncu.edu.cn The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Department of Nephrology Nanchang China -
Gaosi Xu gaosixu@163.com The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University Department of Nephrology Nanchang China -
 
 
 
 
 
 
 
 
 
 
 
 

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with glomerular mesangial cell (MC) proliferation being a central pathological feature. The metabolic reprogramming underlying MC proliferation in IgAN remains poorly understood. Glycine decarboxylase (GLDC), a key metabolic enzyme, promotes proliferation in cancer, but its role in IgAN is unknown. Through bioinformatic analysis, we identified GLDC as a potential key regulator. This study aims to investigate the role and mechanism of GLDC in IgAN pathogenesis.

This study identified GLDC through bioinformatics analysis (WGCNA and KEGG of the GSE141295 dataset) and validated in 49 IgAN patient glomeruli (n=49) via immunohistochemistry/immunofluorescence (IHC/IF). IgAN in vivo model mice were induced by drugs (BSA + LPS + CCL4), and IgA in vitro model in SV40-MES13 cells were induced by polymer IgA (pIgA). Cell proliferation, expressions of inflammatory factors and complement activating molecules in MCs were detected. The construction of GLDC-G776R and GLDC-K759A mutants confirmed the effect of GLDC-dependent enzyme activity on the proliferation of glomerular MCs. Non-target metabolomics analysis in MCs was used to analyze the changes of metabolic pathways after interfering with GLDC, and the interfering plasmids of pyrimidine metabolism rate-limiting enzymes were used for supplementation experiments to verify the regulatory effects of GLDC. Lactate production in MCs, Seahorse extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in human mesangial cells (HMCs) were detected to characterize glycolysis. Inhibition of GLDC in IgAN model mice further verified the effects of GLDC on pyrimidine metabolism, glycolysis and IgAN progression.

GLDC expression was significantly upregulated in IgAN patient glomeruli and specifically localized to MCs, with high expression levels correlating with disease severity (Lee's grade, segmental sclerosis, and tubular atrophy).Figure 1 GLDC was highly expressed in IgAN glomeruli and correlated with disease severity. (A) Representative images of GLDC and PDGFRβ co-staining in renal tissues from IgAN patients across different Lee's grades. (B) Quantification of GLDC co-localization with the mesangial cell marker PDGFRβ and the podocyte marker Podocin, demonstrating specific enrichment in mesangial cells. (C) Summary of the correlation between high GLDC expression and key clinicopathological features (Lee's grade, segmental glomerulosclerosis S1, tubular atrophy/interstitial fibrosis T1-2) in 49 IgAN patients.In vitro, GLDC overexpression promoted MC proliferation, cell cycle progression, and secretion of inflammatory factors (MCP-1, IL-6, C3, TGF-β1, TNF-α), whereas GLDC knockdown reversed these effects.Figure 2 GLDC promotes glomerular mesangial cell proliferation in vitro by driving a process that requires its enzymatic activity. (A) GLDC overexpression enhances, while GLDC knockdown inhibits, pIgA-induced cell proliferation (CCK-8 assay). (B) GLDC overexpression increases, while its knockdown reduces, the protein levels of proliferation markers (PCNA, Cyclin D1). (C-G) GLDC knockdown attenuates pIgA-induced secretion of inflammatory factors (MCP-1, IL-6, TGF-β1, TNF-α) and complement component C3. (H, I) Enzyme-dead GLDC mutants (G776R, K759A) fail to promote cell proliferation (H) and alter cell cycle progression (I), demonstrating the requirement of its metabolic activity.
Crucially, enzyme-dead GLDC mutants (G776R/K759A) failed to promote proliferation, confirming strict enzyme activity dependence. Mechanistically, GLDC enhanced pyrimidine metabolic flux, which subsequently fueled glycolysis—evidenced by increased lactate production and elevated ECAR and OCR. Knockdown of pyrimidine metabolic enzymes (CAD/DHODH) abolished both GLDC-induced glycolysis and proliferation.
Figure 3 GLDC regulates mesangial cell proliferation by activating pyrimidine metabolism, which in turn fuels glycolysis. (A) GLDC knockdown suppresses pyrimidine metabolism in pIgA-stimulated mesangial cells. (B, C) Knockdown of pyrimidine metabolism rate-limiting enzymes (CAD or DHODH) abolishes the pro‑proliferative effect of GLDC overexpression (B) or pIgA stimulation (C). (D, E) GLDC‑induced lactate production is suppressed by inhibition of pyrimidine metabolism under both overexpression (D) and pIgA‑stimulated (E) conditions. (F, G) Real‑time metabolic flux analysis (Seahorse) shows that GLDC increases extracellular acidification rate (ECAR, glycolysis) and decreases oxygen consumption rate (OCR, mitochondrial respiration), which are reversed by CAD or DHODH knockdown.
In vivo, GLDC silencing via AAV-sh-GLDC ameliorated IgAN progression, attenuating glomerular injury, C3 deposition, and macrophage infiltration, while suppressing the pyrimidine-glycolysis pathway.

As a key target of IgAN, GLDC interference inhibited glomerular MC proliferation by inhibiting pyrimidine metabolism and glycolysis, and finally alleviated the progression of IgAN, providing important theoretical basis for the clinical treatment of IgAN.

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