The role of podocyte injury in the pathogenesis of Fabry disease nephropathy

• Published in: Brazilian Journal of Nephrology Vol. 46; no. 3; p. e20240035
• Main Authors: Monte Neto, José Tiburcio do, Kirsztajn, Gianna Mastroianni
• Format: Journal Article
• Language: English
• Published: Brazil Sociedade Brasileira de Nefrologia 01-07-2024
• Subjects: Autophagy; Chronic; Fabry Disease; Fabry Disease - complications; Fabry Disease - pathology; Glomerular Filtration Barrier; Humans; Kidney Diseases - etiology; Kidney Diseases - pathology; Podocyte; Podocytes - pathology; Renal Insufficiency; Review
• ISSN: 0101-2800; 2175-8239
• DOI: 10.1590/2175-8239-JBN-2024-0035en

Renal involvement is one of the most severe morbidities of Fabry disease (FD), a multisystemic lysosomal storage disease with an X-linked inheritance pattern. It results from pathogenic variants in the GLA gene (Xq22.2), which encodes the production of alpha-galactosidase A (α-Gal), responsible for glycosphingolipid metabolism. Insufficient activity of this lysosomal enzyme generates deposits of unprocessed intermediate substrates, especially globotriaosylceramide (Gb3) and derivatives, triggering cellular injury and subsequently, multiple organ dysfunction, including chronic nephropathy. Kidney injury in FD is classically attributed to Gb3 deposits in renal cells, with podocytes being the main target of the pathological process, in which structural and functional alterations are established early and severely. This configures a typical hereditary metabolic podocytopathy, whose clinical manifestations are proteinuria and progressive renal failure. Although late clinical outcomes and morphological changes are well established in this nephropathy, the molecular mechanisms that trigger and accelerate podocyte injury have not yet been fully elucidated. Podocytes are highly specialized and differentiated cells that cover the outer surface of glomerular capillaries, playing a crucial role in preserving the structure and function of the glomerular filtration barrier. They are frequent targets of injury in many nephropathies. Furthermore, dysfunction and depletion of glomerular podocytes are essential events implicated in the pathogenesis of chronic kidney disease progression. We will review the biology of podocytes and their crucial role in regulating the glomerular filtration barrier, analyzing the main pathogenic pathways involved in podocyte injury, especially related to FD nephropathy.