Fibroblast expression of transmembrane protein smoothened governs microenvironment characteristics after acute kidney injury

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-selective Smo is unclear. Here, we report that Smo-specific ablation in fibroblasts reduced tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal cell 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 to AKI. Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could affect nidogen-1 accessibility. Phosphoproteomics revealed that the ‘AKI protector’ Wnt signaling pathway was activated in these kidneys. Mechanistically, nidogen-1 interacted with integrin β1 to induce Wnt in tubules to mitigate AKI. Altogether, our results support that fibroblast-selective Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and offers a robust resource and path to further dissect AKI pathogenesis. Graphical Abstract available at:
This article was originally published in The Journal of Clinical Investigation. The version of record is available at: © 2024, Gui et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit
Gui, Yuan, Haiyan Fu, Zachary Palanza, Jianling Tao, Yi-Han Lin, Wenjian Min, Yi Qiao, et al. “Fibroblast Expression of Transmembrane Protein Smoothened Governs Microenvironment Characteristics after Acute Kidney Injury.” Journal of Clinical Investigation 134, no. 13 (July 1, 2024): e165836.