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Kidney Week

Abstract: FR-PO772

Elevated Expression of Isthmin-1 Impairs Glomeruli Filtration Leading to Proteinuria in CKD

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Gao, Ge, Guangdong Provincial People's Hospital, Guangzhou, China
  • Zhou, Zhongjun, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
Background

The incidence of chronic kidney disease (CKD) accounts for 10 to 13% in adults and is usually accompanied by cardiovascular diseases, exhibiting high morbidity and mortality. We observed upregulated Isthmin-1 (Ism1) in nephropathy models and aging kidneys. Ism1 transgenic (Ism1 Tg) mice exhibited focal segmental glomerular sclerosis (FSGS) and impaired cytoskeleton in podocytes and proteinuria, as shown by podocyte foot process effacement. In contrast, loss of Ism1 can protect mice from undergoing Adriamycin-induced FSGS and cytoskeleton injury in podocytes. However, the mechanism remains unresolved.

Methods

As a secreted protein, Ism1 functions through interacting with receptor to activate or inhibit the downstream signaling. Since ligand-receptor interaction is normally transient and weak, we took advantage of HRP-induced proximity labelling in kidney tissues to search for the potential receptor of Ism1 in glomeruli.

Results

Based on our unbiased screening of receptors with consideration to kidney phenotypes in genetically modified mice, we identified a specific Integrin as a potential receptor of Ism1 in the adult kidney. The interaction between Ism1 and this Integrin was validated in 293T cells. In addition, Ism1 triggered the activation of specific Integrin signaling, leading to the impairment of the podocyte cytoskeleton. We therefore propose that elevated Ism1 results in podocyte cytoskeleton injury by activating Integrin signaling.

Conclusion

Our findings highlight the critical role of Ism1 in the pathogenesis of kidney diseases and provide a novel target for alleviating podocyte injury and CKD.

Funding

  • Private Foundation Support