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

• Published in: The Journal of clinical investigation Vol. 134; no. 13
• Main Authors: Gui, Yuan, Fu, Haiyan, Palanza, Zachary, Tao, Jianling, Lin, Yi-Han, Min, Wenjian, Qiao, Yi, Bonin, Christopher, Hargis, Geneva, Wang, Yuanyuan, Yang, Peng, Kreutzer, Donald L, Wang, Yanlin, Liu, Yansheng, Yu, Yanbao, Liu, Youhua, Zhou, Dong
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01-07-2024
• Subjects: Acute renal failure; Analysis; Apoptosis; Fibroblasts; Health aspects; Integrins; Membrane proteins; Prevention; Proteomics; Risk factors; Stem cells; United States
• ISSN: 0021-9738
• DOI: 10.1172/JCI165836.

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 [beta]1 to induce Wnt in tubules to mitigate AKI. Altogether, our results support that fibroblastselective Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and offers a robust resource and path to further dissect AKI pathogenesis.