Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease

Podocyte injury is a common hallmark of chronic kidney disease (CKD). The podocin-nephrin complex localized in lipid rafts of podocyte is vital to reduce podocyte injury and proteinuria, however, the mechanism underlying its localization remains unclear. This study uncovers an important role of Flot2 in stabilizing the podocin-nephrin complex localized in lipid rafts. We first confirmed that Flot2 was expressed in podocyte and demenstrated that podocyte-specific Flot2 deletion worsen albuminuria, podocyte injury and glomerular pathology in LPS/ADR-induced nephropathy mouse models. Meanwhile, podocyte injury, albuminuria and pathologic aberrance were prevented in podocyte-specific Flot2 overexpression transgenic mice when challenged with LPS or ADR. Further found that Flot2 was vital to recruit podocin and nephrin into rafts and ameliorated podocyte injury. Flot2 and podocin directly interacted with each other via their SPFH domain. Meanwhile, we also showed that Flot-2 is a direct target of Kruppel-like factor (KLF15). Importanly, we observed that Flot2 was downregulated in renal biopsies from patients with podocytopathies and its expression negatively correlated with proteinuria and positively correlated with eGFR, indicating that Flot2 may be a novel therapeutic target for proteinuric kidney disease.

Automated summary

Podocyte injury is a common feature of chronic kidney disease (CKD). Flot2 has been identified as an important factor in stabilizing the podocin-nephrin complex in lipid rafts, reducing podocyte injury and proteinuria. Flot2 interacts with podocin and nephrin, recruits them into rafts, and ameliorates podocyte injury. Furthermore, Flot2 expression is downregulated in renal biopsies from patients with podocytopathies, suggesting its potential as a therapeutic target for proteinuric kidney disease.