The inflammatory pathogenetic pathways of Fabry nephropathy

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.