Stony Brook Research on Glut1 Protein as a Therapeutic Target for Kidney Disease

Targeting and disabling a certain protein essential to transporting glucose properly through cells (Glucose Transporter 1, or Glut1) could be a new way to fight kidney disease, according to a study led by Partha Biswas of the Renaissance School of Medicine (RSOM) at Stony Brook University.

The research, detailed in a paper published in the Journal of Clinical Investigation Insight, is based on a model of one of the most damaging forms of kidney disease.

This image shows glomerular pathology as characterized by proliferation of the structural cells of the kidney's glomeruli (mesangial cells) and Bowman's capsule cell detachment - indicated in shaded areas - in an experimental model of Glomerulonephritis. Image courtesy of Partha Biswas.

Chronic kidney disease (CKD) is a silent killer and a public health crisis. The Centers for Disease Control and Prevention (CDC) estimates that one in seven Americans, or 35.5 million, are affected by CKD. One of the most damaging forms of CKD is called antibody-mediated glomerulonephritis (AGN), a condition in which the body's immune system produces antibodies that attack the basement membrane of the filtering units of the kidney - the glomeruli. This process leads to much inflammation, severe tissue injury, and eventually kidney failure.

The research team used a murine model of AGN to observe the inflammatory process and experiment with the inflammation-induced metabolically reprogrammed immune cells, particularly the neutrophils within the kidney.

"While metabolic reprogramming has already transformed treatment strategies for cancer and autoimmune diseases, it has not been explored as a therapeutic avenue for neutrophils in AGN," said Biswas, lead author and professor in the Department of Microbiology and Immunology in the RSOM.

Using the model, the researchers showed that neutrophils upregulate Glut1 expression and function in the nephritic kidney. Glut1 not only transports glucose into cells in the kidney, but it also plays a crucial role in glucose reabsorption to outside the kidney preventing damage and glucose passing through the kidney into urine.

After showing this higher Glut1 expression in the disease model, the research team demonstrated that Glut1 function in the inflammatory cells is necessary to advance AGN pathology. This occurs during the early stage of AGN and thus leads to increased inflammation and tissue damage.

"Essentially, we uncovered a previously unrecognized mechanism in the AGN disease process," Biswas said. "We then found that by selectively disabling Glut1 in neutrophils there is a dramatic reduction in their tissue-damaging effector functions throughout disease progression."

Partha Biswas

The authors further reported that "while neutrophil-specific Glut1 ablation diminished the expression of tissue-damaging effector molecules in both early and late stages, renal cytokines' and chemokines' production were compromised only in the late stage of disease. Consequently, the Glut1 inhibitor treatment ameliorated renal pathology in AGN mice."

Biswas explained that in total the findings expose a Glut1-powered circuit within neutrophils.

"This circuit is not only central to disease pathology but also highly targetable and positions neutrophil metabolic prevention as a promising, and previously untapped, therapeutic strategy for AGN and potentially other forms of CKD," he said.

The research was supported in part by the National Institutes of Health (NIH) under grants AI59058, AI42354, and AI181831.