Dataset Information

Fibroblast-derived Smoothened governs prognosis of acute kidney injury

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Dong Zhou

PROVIDER: MSV000088609 | MassIVE | Thu Dec 23 06:55:00 GMT 2021

REPOSITORIES: MassIVE

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Publications

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

Gui Yuan Y Fu Haiyan H Palanza Zachary Z Tao Jianling J Lin Yi-Han YH Min Wenjian W Qiao Yi Y Bonin Christopher C Hargis Geneva G Wang Yuanyuan Y Yang Peng P Kreutzer Donald L DL Wang Yanlin Y Liu Yansheng Y Yu Yanbao Y Liu Youhua Y Zhou Dong D

The Journal of clinical investigation 20240507 13

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 p ...[more]

PMID: 38713523

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