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Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

ABSTRACT: Backgrounds: The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, has a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. Methods: Wild-type (WT) and VISTA-deficient (Vsir-/-, KO) mice were treated with nephrotoxic serum to induced acute antibody-mediated glomerulonephritis, and their cytokine and fibrosis profiles were compared. Results: VISTA was highly expressed in kidney macrophages (resident more than infiltrating subset). If VISTA was depleted, tubules suffered further damage after glomerular injury. In damaged Vsir–/– mice, the contact frequency of macrophages with infiltrated T cells increased, and then the immunometabolic characteristics of T cells changed to overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu as more producing interleukin-9, which augmented tubulointerstitial fibrosis and irreversible kidney dysfunction. The blocking antibodies against interferon-γ and interleukin-9 protected above pathological process by VISTA depletion. Conclusions: VISTA is a sentinel protein of kidney macrophages, which prevents tubulointerstitial fibrosis via interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE181163 | GEO | 2021/08/04

REPOSITORIES: GEO

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Project description:Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 albumin-regulated genes differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n=25) could be distinguished from those of control subjects (n=6) based solely upon the expression of these 231 albumin-regulated genes. The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that the all forms of primary glomerulonephritis (n=33) can be distinguished from controls (n=21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with IgA nephropathy (IgAN) RNA from tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix HG-U133A microarrays.

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Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

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