MassIVE MSV000088609

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Fibroblast-derived Smoothened governs prognosis of acute kidney injury

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Description

Although the tubule is the epicenter of damage, kidney fibroblast is increasingly appreciated in governing the prognosis of acute kidney injury (AKI). Smoothened (Smo), a heptahelical transmembrane protein, carries a hedgehog signal to mediate the communications between kidney fibroblasts and tubular epithelium through an undetermined mechanism in AKI. Integrating in vivo, ex vivo, and in vitro approaches with systems biology, we report that Smo-specific ablation in fibroblast preserved kidney function and mitigated tubular cell apoptosis or inflammation after AKI. Loss of Smo in fibroblasts enhanced the activity of perivascular mesenchymal cells. Global proteomics revealed extracellular matrix is a key cellular compartment where significant proteins are distributed, and Nidogen-1 is a prominent basement membrane glycoprotein highly expressed in fibroblast-Smo specific ablation kidneys. Co-immunoprecipitation showed that Smo binds Nidogen-1. Phosphoproteomics identified wnt signaling pathway, the AKI protector, was activated in fibroblast Smo deletion kidneys. In vitro and ex vivo, Nidogen-1 induced wnts and repressed tubular cell apoptosis. Our results suggest that fibroblast-derived Smo dictates AKI fate through cell-matrix-cell interactions and provides open-access data resources to understand AKI pathogenesis better. [doi:10.25345/C5NS23] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Acute kidney injury ; Fibroblast ; Smoothened ; Quantitative proteomics ; Phosphorylation

Contact

Principal Investigators:
(in alphabetical order) 		Dong Zhou, University of Connecticut, School of Medicine, United States
Submitting User: yayu

Publications

Gui Y, Fu H, Palanza Z, Tao J, Lin YH, Min W, Qiao Y, Bonin C, Hargis G, Wang Y, Yang P, Kreutzer DL, Wang Y, Liu Y, Yu Y, Liu Y, Zhou D.
Fibroblast expression of transmembrane protein smoothened governs microenvironment characteristics after acute kidney injury.
J Clin Invest. Epub 2024 May 7.

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