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Kidney Week

Abstract: TH-OR019

Matricellular Protein Tenascin C Has a Protective Effect in Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mao, Xiaoyi, Division of Nephrology, Huashan Hospital, Shanghai, SHANGHAI, China
  • Hao, Chuan-Ming, Division of Nephrology, Huashan Hospital, Shanghai, SHANGHAI, China
Background

Interstitial microenvironment is critical in regulating cell proliferation and injury/repairing process. Tenascin-C is a matricellular protein which is transiently expressed during development and can be re-induced after injury, suggesting a potential role in tissue injury/repairing. The present study examined the role of TNC in acute kidney injury using a ischemia-reperfusion (IR) model.

Methods

A tenascin-C promoter driven inducible CreER2 knock-in mouse line with an eGFP reporter was generated. TNC-CreER+/+ (TNC-/-) mice were used to examine the role of TNC in of AKI.

Results

Following IR, TNC was markedly induced in the interstitium of the kidney as early as 3 hours and peaked at 24-48 hours. To examine the role of TNC in AKI, we used the TNC-CreER+/+ (TNC-/-) mice. Deletion of TNC in mice significantly aggravated IR induced AKI, showing significantly lower survival rate, higher BUN and more severe tubular injury after IR comparing to their wild type littermates.
We Then examined the mechanism by which TNC is induced following injury. Four hypoxic response elements (HRE) were identified in the promoter region of TNC, suggesting a role of hypoxia-inducible factor(HIF). DMOG, a HIF stabilizer, significantly induced TNC expression both in mice and in primary cultured renal interstitial cells. Luciferase reporter assay showed that hif-2α promoted the transcription of TNC, while mutation of the HRE of the TNC luciferase reporter abolished this effect. The bindiong of hif-2α to endogenous TNC promoter was also supported by ChiP assay.
To explore the mechanism by which TNC protects kidney from AKI, we isolated the primary tubular epithelial cells and treated the cells with commercially available TNC protein. TNC protected primary tubular epithelial cells from hypoxic injury. Our further experiments suggest that the EGF-like domain in TNC was involved in the protective effect via EGFR-STAT3 pathway.

Conclusion

TNC, which is immediately induced following IR, has a protective effect on ischemia-reperfusion injury.