Abstract: TH-PO324
Tenascin-C Mediates the Protective Effect of HIF in AKI
Session Information
- AKI: Repair and Regeneration
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 002 AKI: Repair and Regeneration
Authors
- Mao, Xiaoyi, Division of Nephrology, Huashan Hospital, Shanghai, China
- Xie, Qionghong, Division of Nephrology, Huashan Hospital, Shanghai, China
- Zhang, Min, Division of Nephrology, Huashan Hospital, Shanghai, China
- Shang, Da, Division of Nephrology, Huashan Hospital, Shanghai, China
- Hao, Chuan-Ming, Division of Nephrology, Huashan Hospital, Shanghai, China
Background
Accumulating evidence suggests that the hypoxia-inducible factor (HIF) mediates cellular adaptions to hypoxia and has a protective effect in acute kidney injury, but the mechanism is not completely understood. The matricellular protein tenascin-C(TNC) which is transiently expressed during development can be re-induced after tissue injury and may be involved in creating a microenvironment that facilitates cell proliferation, adhesion and inflammation. The present study examined the role of TNC in mediating the protective effect of HIF in acute kidney injury using 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. RNA sequencing was performed to analyze differentially expressed genes between TNC-/- mice and their wild type littermates.
Results
Following IR, TNC was markedly induced in the interstitium of corticomedullary junction of the kidney as early as 3 hours and peaked at 24-48 hours. Increased TNC expression was also observed in biopsy tissues from patients with AKI. Deletion of TNC in mice significantly aggravated IR induced AKI, showing lower survival rate, higher BUN and more severe tubular injury comparing to their wild type littermates.
Then the mechanism underlying TNC induction following injury was investigated. Since 4 hypoxic response elements (HRE) were identified in the promoter region of TNC, we examined the effect of HIF on TNC induction. 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.
To explore the mechanism by which TNC protects kidney from AKI, we did RNA sequencing using renal tissues of TNC-/- mice and their wild type littermates 2 days after IR. RNA-Seq data showed that TNC-/- mice had lower levels of pro-inflammatory cytokines, chemokines and their receptors than wild type mice. Our data suggested that TNC might play an important role in the recovery phase of IR by activating inflammatory response.
Conclusion
Hif-2α induced expression of TNC after ischemia-reperfusion and TNC facilitated recovery from IR injury by activating inflammatory response.