Divergent stage-specific regulation of neutrophil function by glucose transporter 1 in murine antibody-mediated glomerulonephritis
Hossein Rahimi, Wonseok Choi, Doureradjou Peroumal, Shuxia Wang, Partha S. Biswas
Hossein Rahimi, Wonseok Choi, Doureradjou Peroumal, Shuxia Wang, Partha S. Biswas
View: Text | PDF
Research Article Immunology Inflammation Nephrology

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

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.

Authors

Hossein Rahimi, Wonseok Choi, Doureradjou Peroumal, Shuxia Wang, Partha S. Biswas

×

Figure 3

Neutrophil-specific Glut1 function reduces kidney damage in AGN.

Options: View larger image (or click on image) Download as PowerPoint
Neutrophil-specific Glut1 function reduces kidney damage in AGN. (A) Sch...
(A) Schematic diagram of the experiment. BM cells from ERT2Cre+ Slc2a1fl/fl (CD45.2+) and WT (CD45.1+) mice were transferred into sublethally irradiated (9 Gy) ERT2Cre+ Slc2a1fl/fl or WT recipients (n = 5). Eight weeks later, reconstituted mice were injected with 4 consecutive injections of TAM before being subjected to AGN. Representative flow cytometry contour plots showing reconstitution efficiency in the blood of recipient mice. At day 14 after anti-GBM serum injection, mice were assessed for kidney dysfunction by measuring serum (B) BUN and (C) creatinine levels. (D) Renal pathology (n = 5) was blindly evaluated and scored for percentages of abnormal glomeruli, crescent formation, and tubular inflammation following PAS staining of kidney sections. Data representative of 1 of 5 mice/group. Magnification: glomerular pathology: 600×; tubular inflammation: 400×. A small part (as indicated by dotted lines) of the original image was shown as inset panels. Black star: mesangial cell proliferation; black pound sign: glomerular atrophy. Control and PMNGlut1 mice (n = 6) were subjected to AGN. At day 14 after anti-GBM serum injection, (E) in vivo glucose uptake, (F) serum BUN and (G) creatinine, and (H) renal Kim1 mRNA levels were measured. (I) Renal pathology was evaluated and scored for percentages of abnormal glomeruli, crescent formation, and tubular inflammation following PAS staining. Data representative of 1 of 5 mice/group for I. Magnification: glomerular pathology: 600×; tubular inflammation: 400×. A small part (as indicated by dotted lines) of the original image was shown as inset panels. Black star: mesangial cell proliferation; black plus sign: partial segmental glomerulosclerosis. Data pooled from at least 2 independent studies (B–I). Each dot represents an individual mouse, and data are expressed as mean ± SD. Statistical analysis by 1-way ANOVA (B–I). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.