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Abstract: PO0437

Extracellular Matrix Protein 1 Organized Microenvironment Keys to Kidney Repair After AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gui, Yuan, University of Connecticut School of Medicine, Farmington, Connecticut, United States
  • Zhou, Dong, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background

In AKI, the kidney tubule is well-known as the epicenter of damages, yet little attention has been paid to changes in the microenvironment and associated repair processes. Amid this process, the extracellular matrix (ECM) is the principal organizing component for microenvironment construction and tubule repair, serving as a scaffold for remodeling. How ECM interacts with its surrounding materials to dictate the prognosis of AKI remains unclear in the field.

Methods

Kidney ischemia-reperfusion injury was employed to induce AKI in mice. In vivo, in vitro, and ex vivo translational experiments and quantitative proteomic analyses were performed.

Results

Quantitative proteomics revealed that extracellular matrix protein 1 (ECM-1) was the earliest activated matrix protein in ischemic AKI kidneys. Immunostaining revealed that ECM-1 was predominantly expressed in the activated kidney fibroblasts. In cultured fibroblast, knockdown ECM1 markedly repressed cell activation and proliferation, as assessed by the decreased expression of α-SMA, vimentin, PDGFR-β, and PCNA. Ex vivo, knockdown ECM1 in the decellularized AKI kidney scaffold directly reduced its capacities in promoting the proliferation of the seeded tubular cells. In vivo, loss of ECM1 caused elevated serum creatinine levels, more severe morphologic changes, and reduced inductions of α-SMA, vimentin, and PDGFR-β than the controls after AKI. By using affinity-purification mass spectrometry, we identified a vital mechanism that ECM1 could bind to an essential tubule-derived growth factor protecting against AKI, sonic hedgehog (Shh). In vitro, we confirmed that recombinant ECM1 promoted tubular cell proliferation and Shh expression.

Conclusion

Our finding implicated that ECM1 created a favorable microenvironment by interacting with Shh to promote AKI recovery.

Funding

  • NIDDK Support