Pathogenesis of Fabry nephropathy: the pathways leading to fibrosis

ROZENFELD, PAULA; BOLLA, MARÍA DE LOS ÁNGELES; QUIETO, PEDRO; PISANI, A; FERIOZZI, S; NEUMAN, PABLO; BONDAR, CONSTANZA

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2020

1096-7192

AbstractBackgroundKidneyis one of the main target organs in Fabry disease, a lysosomal X-linked geneticdisorder. Renal involvement is characterized by proteinuria and progressivechronic kidney disease leading to end-stage renal disease. Pathogenicmechanisms in the progression of renal damage in Fabry disease are not thoroughlyknown yet. The lysosomal Gb3 deposition is the first step of complexpathological pathways resulting in renal sclerosis/fibrosis. Our hypothesis isthat Fabry disease associated cellular alterations in tubular cells induce the productionof TGF-β1, which mediate transdifferentiation of renal cells intomyofibroblasts resulting in fibrosis of renal tissue. ObjectivesThe aimof this work is to study the mechanisms leading to fibrosis in kidney fromhuman Fabry patients.MethodsFifteenrenal biopsies from naïve Fabry patients were included. Histological andimmunohistochemical analysis was carried out.ResultsPositive staining for TGF-β1 was found in tubularepithelial cells in biopsies from Fabry patients. Apoptosis wasdetermined by active caspase 3 staining in tubular and mesangial glomerularcells. Due to TGF-β1 is the main profibrotic cytokine and induces accumulationof myofibroblasts, we performed a study for its marker α-smooth muscle actin(α-SMA). This study revealed expression of α-SMA on pericytes surroundingperitubular capillaries, smooth muscle cells of blood vessels, mesangial cellsand periglomerular zone. TGF-β1 is produced mainly by tubular cells in Fabrykidney biopsies probably inducing cellular trans-differentiation of renal cellsinto myofibroblasts. A positive staining for a marker of myofibroblasts waspresent, affirming the presence of those profibrotic cells. ConclusionsTheseresults show for the first time that TGF- β1 is expressed in human renal tissuefrom Fabry patients, and that this profibrotic cytokine is mainly produced by proximaltubular cells. In addition both, peritubular interstitium and glomeruli,presented cells positive for myofibroblasts markers.