Abstract: SA-PO097
Proximal Tubular FHL2 Protects Against Ischemia/Reperfusion-Induced AKI via HIF-1 and β-Catenin Signaling
Session Information
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wang, Yan, 2nd Affiliated hospital of NJMU, Nanjing, Jiangsu, China
- He, Weichun, 2nd Affiliated hospital of NJMU, Nanjing, Jiangsu, China
Background
Hypoxia inducible factor 1 (HIF-1) and β-catenin signaling pathways activated in proximal tubular epithelial cells (PTECs) play an important role in regulating cell proliferation and apoptosis during acute kidney injury (AKI). Four-and-a-half LIM domains protein 2 (FHL2), an adaptor protein, has been demonstrated involving in HIF-1 and β-catenin signaling, respectively. However, the potential effect of FHL2 on AKI remains to be elucidated.
Methods
The expression of FHL2 in PTECs was examined in AKI induced by bilateral ischemia reperfusion (I/R) in mice and in NRK-52E (rat PTECs) cultured in hypoxia/reoxygenation (H/R) conditions, respectively. Mice with PTECs-specific deletion of FHL2 (Tubule-FHL2-/-) were generated by mating FHL2-floxed mice with Ggt1-Cre transgenic mice. The function of FHL2 in PTECs during AKI was investigated in Tubule-FHL2-/- mice after I/R.
Results
The expression of FHL2 was upregulated in PTECs during AKI in vivo. Compared with control littermates, Tubule-FHL2-/- mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death, inflammatory cell infiltration and less tubular cell proliferation after I/R. The activation of both HIF-1 and β-catenin signaling pathways was attenuated in Tubule-FHL2-/- mice after I/R comparing with control littermates. In vitro, the induction of FHL2 was correlated with upregulation of HIF-1α. Two functional hypoxia responsive elements was identified in the promoter region of FHL2 gene, which interacted with HIF-1α under hypoxia conditions, suggesting that FHL2 is a novel direct target gene of HIF-1. Overexpression of FHL2 induced physical interactions between FHL2 and HIF-1α and between FHL2 and β-catenin, which promoted HIF-1α and β-catenin nuclear translocation, and enhanced the transcriptional activity of their downstream targets, respectively.
Conclusion
Our results suggest that FHL2, as a downstream target gene of HIF-1, plays a critical protective role in AKI through regulating the activities of HIF-1 and β-catenin signaling pathways simultaneously, and FHL2 could be a potential future therapeutic target for AKI.
Funding
- Government Support – Non-U.S.