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Published on: November 10, 2021
Pathogenic pathways of renal damage in Fabry nephropathy: interplay between immune cell infiltration, apoptosis and
Constanza Bondar1, Maria de Los Angeles de Bolla2, Pablo Neumann3
1Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, CONICET, Asociado CIC PBA, Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), Universidad Nacional de La Plata, Bv 120 Nro 1489, 47 y 115, 1900, La Plata, Argentina.
Background:
Fabry nephropathy is a consequence of the deposition of globotriaosylceramide, caused by deficient GLA enzyme activity in all types of kidney cells. These deposits are perceived as damage signals leading to activation of inflammation resulting in renal fibrosis. There are few studies related to immunophenotype characterization of the renal infiltrate in kidneys in patients with Fabry disease and its relationship to mechanisms of fibrosis. This work aims to quantify TGF-β1 and active caspase 3 expression and to analyze the profile of cells in inflammatory infiltration in kidney biopsies from Fabry naïve-patients, and to investigate correlations with clinical parameters.
Methods:
Renal biopsies from 15 treatment-naïve Fabry patients were included in this study. Immunostaining was performed to analyze active caspase 3, TGF-β1, TNF-α, CD3, CD20, CD68 and CD163. Clinical data were retrospectively gathered at time of kidney biopsy.
Results:
Our results suggest the production of TNFα and TGFβ1 by tubular cells, in Fabry patients. Active caspase 3 staining revealed that tubular cells are in apoptosis, and apoptotic levels correlated with clinical signs of chronic kidney disease, proteinuria, and inversely with glomerular filtration rate. The cell infiltrates consisted of macrophages, T and B cells. CD163 macrophages were found in biopsy specimens and their number correlates with TGFβ1 and active caspase 3 tubular expression.
Conclusions:
These results suggest that CD163+ cells could be relevant mediators of fibrosis in Fabry nephropathy, playing a role in the induction of TGFβ1 and apoptotic cell death by tubular cells. These cells may represent a new player in the pathogenic mechanisms of Fabry nephropathy.
Insights
In Fabry nephropathy, CD163+ macrophages contribute to kidney fibrosis by inducing TGF-β1 and tubular cell apoptosis. This finding highlights a new mechanism in Fabry disease pathogenesis.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Fabry nephropathy involves globotriaosylceramide deposition due to deficient GLA enzyme activity, triggering inflammation and renal fibrosis.
- Limited research exists on the renal infiltrate immunophenotype and its link to fibrosis mechanisms in Fabry disease.
- This study investigates inflammatory cell profiles and their correlation with fibrosis markers in Fabry nephropathy.
Purpose of the Study:
- Quantify TGF-β1 and active caspase 3 expression in kidney biopsies from treatment-naïve Fabry patients.
- Analyze the immunophenotype of inflammatory cell infiltrates in Fabry nephropathy.
- Correlate cellular and molecular findings with clinical parameters of kidney disease.
Main Methods:
- Immunohistochemical analysis of active caspase 3, TGF-β1, TNF-α, CD3, CD20, CD68, and CD163 in renal biopsies.
- Inclusion of 15 treatment-naïve Fabry patients.
- Retrospective collection of clinical data at the time of kidney biopsy.
Main Results:
- Tubular cells in Fabry patients produce TNFα and TGFβ1.
- Apoptotic tubular cells (active caspase 3+) correlate with chronic kidney disease severity, proteinuria, and inversely with GFR.
- Inflammatory infiltrates comprise macrophages, T cells, and B cells, with CD163+ macrophages correlating with TGFβ1 and active caspase 3 expression.
Conclusions:
- CD163+ macrophages are implicated as key mediators of fibrosis in Fabry nephropathy.
- These macrophages may induce TGFβ1 production and tubular cell apoptosis, contributing to Fabry disease progression.
- CD163+ macrophages represent a novel cellular player in the pathogenesis of Fabry nephropathy.
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