Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1

Focal and segmental glomerulosclerosis, or renal scarring, is a debilitating disease. The identification of the molecular mechanisms of its initiation and progression has been limited, thus hampering the development of proper animal models. Dontscho Kerjaschki and his colleagues now report that microRNA-193a is elevated in human cases of the disease and that transgenic expression in mice is sufficient to cause the condition. Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. We report that transgenic expression of the microRNA miR-193a in mice rapidly induces FSGS with extensive podocyte foot process effacement. Mechanistically, miR-193a inhibits the expression of the Wilms' tumor protein (WT1), a transcription factor and master regulator of podocyte differentiation and homeostasis. Decreased expression levels of WT1 lead to downregulation of its target genes PODXL (podocalyxin) and NPHS1 (nephrin), as well as several other genes crucial for the architecture of podocytes, initiating a catastrophic collapse of the entire podocyte-stabilizing system. We found upregulation of miR-193a in isolated glomeruli from individuals with FSGS compared to normal kidneys or individuals with other glomerular diseases. Thus, upregulation of miR-193a provides a new pathogenic mechanism for FSGS and is a potential therapeutic target.