Pathogenesis of Fabry nephropathy: the pathways leading to fibrosis

ROZENFELD PA; PISANI A; BONDAR C; QUIETO P; NEUMANN P; BOLLA M; FERIOZZI S

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020

1096-7192

Background: Kidney is one of the main target organs in Fabry disease, a lysosomal X-linked genetic disorder.Renal involvement is characterized by proteinuria and progressive chronic kidney disease leading to end-stagerenal disease. Pathogenic mechanisms in the progression of renal damage in Fabry disease are not thoroughlyknown yet. The lysosomal Gb3 deposition is the first step of complex pathological pathways resulting in renalsclerosis/fibrosis. Our hypothesis is that Fabry disease associated cellular alterations in tubular cells induce theproduction of TGF-β1, which mediate transdifferentiation of renal cells into myofibroblasts resulting in fibrosisof renal tissue.Objectives: The aim of this work is to study the mechanisms leading to fibrosis in kidney from human Fabrypatients.Methods: Fifteen renal biopsies from naïve Fabry patients were included. Histological and immunohistochemicalanalysis was carried out.Results: Positive staining for TGF-β1 was found in tubular epithelial cells in biopsies from Fabry patients.Apoptosis was determined by active caspase 3 staining in tubular and mesangial glomerular cells. Due to TGF-β1is the main profibrotic cytokine and induces accumulation of myofibroblasts, we performed a study for itsmarker α-smooth muscle actin (α-SMA). This study revealed expression of α-SMA on pericytes surroundingperitubular capillaries, smooth muscle cells of blood vessels, mesangial cells and periglomerular zone.TGF-β1 is produced mainly by tubular cells in Fabry kidney biopsies probably inducing cellular trans-differentiationof renal cells into myofibroblasts. A positive staining for a marker of myofibroblasts was present,affirming the presence of those profibrotic cells.Conclusions: These results show for the first time that TGF-β1 is expressed in human renal tissue from Fabrypatients, and that this profibrotic cytokine is mainly produced by proximal tubular cells. In addition both,peritubular interstitium and glomeruli, presented cells positive for myofibroblasts markers