# Divergent stage-specific regulation of neutrophil function by glucose transporter 1 in murine antibody-mediated glomerulonephritis

## TL;DR

This study shows that glucose transporter 1 in neutrophils plays a key role in kidney damage during a type of kidney disease, and targeting it could help treat the condition.

## Contribution

The study reveals a new role for neutrophil-specific Glut1 in driving inflammation and kidney damage in antibody-mediated glomerulonephritis.

## Key findings

- Neutrophils increase Glut1 expression and function in the nephritic kidney.
- Neutrophil-specific Glut1 is critical for tissue-damaging effector molecule expression in AGN.
- Glut1 inhibition reduces renal pathology in a mouse model of AGN.

## Abstract

Prolonged and dysregulated neutrophilic inflammation causes tissue damage in chronic inflammatory diseases, including antibody-mediated glomerulonephritis (AGN). An increase in glycolysis, supported by enhanced glucose uptake, is a hallmark of hyperneutrophilic inflammation. Neutrophils upregulate glucose transporter 1–mediated (Glut1-mediated) glucose incorporation for renal antimicrobial activities. However, little is known about the role of neutrophil-specific Glut1 function in the pathogenesis of AGN. Using a well-vetted mouse model of AGN, we show that neutrophils upregulate Glut1 expression and function in the nephritic kidney. We demonstrate that Glut1 function in the hematopoietic cells during the early stage of the disease is necessary for kidney pathology. Most importantly, neutrophil-intrinsic Glut1 function is critical for AGN. While neutrophil-specific Glut1 ablation diminished the expression of tissue-damaging effector molecules in both the early and late stages, renal cytokines’ and chemokines’ production were compromised only in the late stage of the disease. Consequently, Glut1 inhibitor treatment ameliorated renal pathology in AGN mice. These data identify a Glut1-driven inflammatory circuit in neutrophils, which is amenable to therapeutic targeting in AGN.

This report describes how increased glucose metabolism drives the tissue-damaging function of neutrophils in chronic kidney diseases.