Fibroblast-selective smoothened governs the prognosis of acute kidney injury

Abstract The smoothened (Smo) receptor facilitates hedgehog signaling between kidney fibroblasts and tubules during acute kidney injury (AKI). Tubule-derived hedgehog is protective in AKI, but the role of fibroblast-derived Smo is unclear. Here, we report that Smo ablation in fibroblasts mitigated tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal activities, and preserved kidney function after AKI. Global proteomics of these kidneys identified extracellular matrix proteins, and nidogen-1 glycoprotein in particular, as key response markers; Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could impact nidogen-1 accessibility. Phosphoproteomics revealed that the ‘AKI protector’ Wnt pathway was activated in these kidneys, and in vitro and ex vivo, nidogen-1 was able to induce Wnts and repress tubular cell apoptosis. Altogether, our results support that fibroblast-derived Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and establish a robust resource and path to further dissect AKI pathogenesis.