Universidade Federal do Piauí, Departamento de Clínica Geral, Teresina, PI, Brazil.
Universidade Federal de São Paulo, Departamento de Medicina, São Paulo, SP, Brazil.
J Bras Nefrol. 2024 Jul-Sep;46(3):e20240035. 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.
肾脏受累是法布里病（FD）最严重的并发症之一，FD 是一种具有 X 连锁遗传模式的多系统溶酶体贮积病。它是由 GLA 基因（Xq22.2）的致病变异引起的，该基因编码产生α-半乳糖苷酶 A（α-Gal），负责糖鞘脂代谢。这种溶酶体酶的活性不足会产生未加工的中间底物的沉积物，特别是神经节苷脂 Gb3 和衍生物，引发细胞损伤，随后导致多个器官功能障碍，包括慢性肾病。FD 中的肾脏损伤通常归因于肾脏细胞中的 Gb3 沉积物，足细胞是病理过程的主要靶标，其中结构和功能改变很早就很严重。这构成了一种典型的遗传性代谢性足细胞病，其临床表现为蛋白尿和进行性肾功能衰竭。尽管这种肾病的晚期临床结局和形态变化已经得到很好的确定，但触发和加速足细胞损伤的分子机制尚未完全阐明。足细胞是高度特化和分化的细胞，覆盖肾小球毛细血管的外表面，在维持肾小球滤过屏障的结构和功能方面发挥着关键作用。它们是许多肾脏病中损伤的常见靶点。此外，肾小球足细胞的功能障碍和耗竭是慢性肾脏病进展发病机制中的重要事件。我们将回顾足细胞的生物学及其在调节肾小球滤过屏障中的关键作用，分析涉及足细胞损伤的主要致病途径，特别是与 FD 肾病相关的途径。
