Mann Nina, Sun Hua, Majmundar Amar J
Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Pediatr Nephrol. 2025 May;40(5):1523-1538. doi: 10.1007/s00467-024-06551-x. Epub 2024 Nov 1.
Glomerular diseases are a leading cause of chronic kidney disease worldwide. Both acquired and hereditary glomerulopathies frequently share a common final disease mechanism: disruption of the glomerular filtration barrier, podocyte injury, and ultimately podocyte death and detachment. Over 70 monogenic causes of proteinuric kidney disease have been identified, and most of these genes are highly expressed in podocytes, regulating key processes such as maintenance of the slit diaphragm, regulation of actin cytoskeleton remodeling, and modulation of downstream transcriptional pathways. Collectively, these are increasingly being referred to as hereditary "podocytopathies," in which podocyte injury is the central feature driving proteinuria and kidney dysfunction. In this review, we provide an overview of the monogenic podocytopathies and discuss the molecular mechanisms by which single-gene defects lead to podocyte injury and ultimately glomerulosclerosis. We review how advances in genomic technology and a better understanding of the cell biological basis of disease have led to the development of more targeted and personalized therapeutic strategies, including an overview of small molecule and gene therapy approaches.
肾小球疾病是全球慢性肾脏病的主要病因。获得性和遗传性肾小球病常常具有共同的最终疾病机制：肾小球滤过屏障破坏、足细胞损伤，最终导致足细胞死亡和脱落。已确定70多种导致蛋白尿性肾病的单基因病因，其中大多数基因在足细胞中高度表达，调节关键过程，如裂孔隔膜的维持、肌动蛋白细胞骨架重塑的调节以及下游转录途径的调控。总的来说，这些疾病越来越多地被称为遗传性“足细胞病”，其中足细胞损伤是导致蛋白尿和肾功能障碍的核心特征。在这篇综述中，我们概述了单基因足细胞病，并讨论了单基因缺陷导致足细胞损伤并最终导致肾小球硬化的分子机制。我们回顾了基因组技术的进展以及对疾病细胞生物学基础的更好理解如何推动了更具针对性和个性化治疗策略的发展，包括小分子和基因治疗方法的概述。
