The inflammatory pathogenetic pathways of Fabry nephropathy

Abstract

The high variability in clinical features and outcomes observed in monogenic diseases such as Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Research indicates that the deposition of Gb3 and lyso-Gb3 can stimulate inflammatory processes. Immune-competent mononuclear cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as interleukin-1β, tumor necrosis factor-α, and transforming growth factor-β. This culminates in the activation of inflammatory cascades associated with oxidative stress and apoptotic mechanisms maintained by renal resident and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, from another angle (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 the deposition of Gb3 and lyso-Gb3 can become independent of the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or after 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 summarize the available evidence on the pathogenesis of renal damage.

Keywords

Fabry nephropathy / inflammation / pathogenetic mechanisms

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