# Glycine decarboxylase advances IgA nephropathy by boosting mesangial cell proliferation through the pyrimidine pathway

## TL;DR

This study shows that a protein called GLDC worsens IgA kidney disease by boosting cell growth through a metabolic pathway, suggesting GLDC could be a new treatment target.

## Contribution

The study identifies GLDC as a novel driver of IgA nephropathy progression via pyrimidine metabolism and glycolysis.

## Key findings

- GLDC expression is elevated in IgAN glomeruli and correlates with disease severity.
- GLDC knockdown reduces mesangial cell proliferation and inhibits pyrimidine metabolism.
- Inhibiting GLDC in vivo alleviates IgAN progression by reducing kidney damage and inflammation.

## Abstract

The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC’s regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.

This study reveals that glycine decarboxylase (GLDC) promotes IgA nephropathy (IgAN) progression by enhancing mesangial cell proliferation through the pyrimidine pathway. GLDC’s inhibition of pyrimidine metabolism and glycolysis could offer a new therapeutic approach for IgAN.

GLDC expression was significantly elevated in IgAN glomeruli correlating with disease severity.Knockdown of GLDC reduced mesangial cell proliferation and inhibited pyrimidine metabolism.GLDC regulated glycolysis, influencing the progression of renal fibrosis in IgAN.In vivo silencing of GLDC alleviated IgAN progression by reducing glomerular damage and inflammation.Targeting GLDC or its metabolic pathways may provide a novel therapeutic strategy for IgAN.

GLDC expression was significantly elevated in IgAN glomeruli correlating with disease severity.

Knockdown of GLDC reduced mesangial cell proliferation and inhibited pyrimidine metabolism.

GLDC regulated glycolysis, influencing the progression of renal fibrosis in IgAN.

In vivo silencing of GLDC alleviated IgAN progression by reducing glomerular damage and inflammation.

Targeting GLDC or its metabolic pathways may provide a novel therapeutic strategy for IgAN.

This study reveals that glycine decarboxylase (GLDC) promotes IgA nephropathy (IgAN) progression by enhancing mesangial cell proliferation through the pyrimidine pathway. GLDC’s inhibition of pyrimidine metabolism and glycolysis could offer a new therapeutic approach for IgAN.