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Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 Rare Disease and
DOI: 10.20517/rdodj.2023.37
Orphan Drugs Journal

Review Open Access

The inflammatory pathogenetic pathways of Fabry
nephropathy

Sandro Feriozzi 1 , Paula Rozenfeld 2
1
Department of Nephrology and Dialysis, Belcolle Hospital, Viterbo 01100, Italy.
2
Departamento de Ciencias Biológicas, Instituto de Estudios Inmunológicos y Fisiopatológicos [IIFP], UNLP, CONICET, Asociado
CIC PBA, Facultad de Ciencias Exactas, La Plata 1900, Argentina.
Correspondence to: Prof. Sandro Feriozzi, Department of Nephrology and Dialysis, Belcolle Hospital, Via Sammartinese, snc,
Viterbo 01100, Italy. E-mail: sandro.feriozzi@asl.vt.it

How to cite this article: Feriozzi S, Rozenfeld P. The inflammatory pathogenetic pathways of Fabry nephropathy. Rare Dis Orphan
Drugs J 2024;3:11. https://dx.doi.org/10.20517/rdodj.2023.37

Received: 30 Sep 2023 First Decision: 16 Jan 2024 Revised: 2 Feb 2024 Accepted: 8 Apr 2024 Published: 18 Apr 2024
Academic Editor: Daniel Scherman Copy Editor: Fangling Lan Production Editor: Fangling Lan

Abstract
The high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggests
the presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3.
Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes.
Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and release
pro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation of
inflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents and
infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry
(termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-
galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response
(UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-
inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated
that the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from the
initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-
therapy or gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest
in the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of these
processes in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renal
damage.

Keywords: Fabry nephropathy, inflammation, pathogenetic mechanisms

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0
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