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Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37 Page 5 of 11

Indeed, urinary proteomics displayed high levels of uromodulin, prostaglandins, podocalyxin, and fibroblast
growth factor 23, and ERT is associated with reducing the urinary levels of these molecules [34,35] .

The glomerular capillaries can be considered highly differentiated vascular structures, and the endothelium
is a target of Gb3 deposition. Gb3 exposure determines oxidative stress and overexpression of adhesion
molecules, and it is associated with the oxidation of many molecules, such as DNA, lipids, and proteins,
[36]
resulting in cellular dysfunction . More-over, Gb3 causes the deregulation of many endothelial pathways,
such as endothelial nitric oxide synthase [eNOS], with decreased oxide bioavailability or enzyme
[37]
uncoupling and increased pro-inflammatory cytokines cyclooxygenase mediated . In larger vessels, Lyso-
Gb3 also induces the proliferation of smooth muscle cells that, in addition to the oxidative processes,
[38]
determine a thickening of the vascular wall and indirect issues of ischemia .

Finally, an imbalance between molecules inhibiting neovascularization [thrombospodin-1], fibroblast
growth factor and proangiogenic elements [eNOS, angiopoietin2] was described in Fabry patients,
highlighting the role of vascular structures in FN .
[39]

THE INFLAMMATORY PROCESSES AND TUBULE-INTERSTITIAL RESPONSE
Tubular interstitium has a pathogenic role in Fabry nephropathy, although the related clinical signs are
mild . Like every kidney cell type, tubular cells are affected by exposure to glycolipid deposits . Tubular
[41]
[40]
cells are dividing cells with high metabolic expenditure and energy consumption, one of the cell types with
the highest numbers of mitochondria per cell in the body .
[42]
[17]
In vitro studies with tubular cell lines showed mitochondrial dysfunction , increased autophagy and
reactive oxygen species [ROS] production, as well as proapoptotic signaling . As the tubular system of the
[18]
kidney is highly dependent on mitochondrial function to uphold the transcellular transport of solutes and
active secretion of compounds into the urine, dysfunction of the central energy metabolism can result in
harmful effects. Moreover, in vitro exposure to Gb3 and Lyso-Gb3 of the epithelial tubular cell line, HK2,
resulted in transdifferentiation to myofibroblasts, displaying a profibrotic profile .
[43]
The contribution of the tubular compartment to pathogenesis could also be assumed by studies with mouse
models. Observations in the mouse model developed by cross-breeding the GLA-KO with Gb3 synthase
transgenic mice [GLA-KO-Tg] revealed tubular glycolipid injury that affects renal function, with
[44]
polyuria, polydipsia, and decreased urine osmolality, without remarkable glomerular damage .
[45]

Studies on renal biopsies from human Fabry patients highlighted the tubular system. The main profibrotic
[6]
cytokine, TGFβ, is produced by proximal tubular cells . This profibrotic environment induces
transdifferentiation of epithelial cells into fibroblasts that were shown to be present in pericytes surrounding
peritubular capillaries, mesangial cells, and the periglomerular zone. Therefore, tubular cells could be the
cells in which pathological profibrotic changes are initiated. After this insult commences, it spreads to other
renal areas, leading to fibrotic deposition in the glomerulus and interstitium . In a recent study,
[30]
Turkmen et al. analyzed the subpopulations of immune infiltrating cells in renal biopsies from a small
group of Fabry patients at baseline and under enzymatic replacement therapy [ERT] . This study revealed
[46]
a reduction in CD8, CD16, T cells, and NK cells and an increase in CD20 B cells and CD38 plasma cells,
indicating the interstitial immune infiltrating cells’ active participation in the inflammation and the
subsequent renal damage.