Isthmin-1 (Ism1) modulates renal branching morphogenesis and mesenchyme condensation during early kidney development

Abstract

The outgrowth of epithelial bud followed by reiterated bifurcations during renal development is driven by the ligand-receptor interactions between the epithelium and the surrounding mesenchyme. Here, by exploring ligand-receptor interactions in E10.5 and E11.5 kidneys by single cell RNA-seq, we find that Isthmin1 (Ism1), a secreted protein, resembles Gdnf expression and modulates kidney branching morphogenesis. Mice deficient for Ism1 exhibit defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation in E11.5 embryos, attributable to the compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia. By HRP-induced proximity labelling, we further identify integrin α8β1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin α8β1, the receptor whose activation is responsible for Gdnf expression and mesenchyme condensation. Taken together, our work reveals Ism1 as a critical regulator of cell-cell interaction that modulates Gdnf/Ret signaling during early kidney development.

Glomerular filtration rate in patients with type 2 diabetes mellitus: is serum isthmin-1 level a possible link?

“…Gao et al found that Ism-1 plays a critical role in early kidney development. Ism-1 knockout mice failed in branching morphogenesis and mesenchyme condensation 30. Both podocyte impair and tubulointerstitial changes are important in DKD development 31 32.…”

“…Ism-1 knockout mice failed in branching morphogenesis and mesenchyme condensation. 30 Both podocyte impair and tubulointerstitial changes are important in DKD development. 31 32 Further mechanistic studies are required to elucidate the relationship between Ism-1 and impaired kidney function.…”