Abstract: FR-PO162
Histone Methyltransferase SMYD2 Promotes AKI and Renal Regeneration by Activating Epidermal Growth Factor Receptors
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Hou, Xiying, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Zhuang, Shougang, Department of Medicine, Rhode Island Hospital, Providence, Rhode Island, United States
Background
Protein methyltransferase SET and MYND domain containing protein 2 (SMYD2) is one of the most widely studied lysine methyltransferases. It is involved in the development of numerous tumors and renal fibrosis by inducing methylation of H3K36 and H3K4 as well as multiple non-histone protiens, but its role in acute kidney injury (AKI) remains unclear.
Methods
In this study, we investigated the role and mechanism of SMYD2 in murine models of AKI induced by folic acid (FA), ischemia/reperfusion (I/R), as well as cecal ligation and puncture (CLP) using highly selective inhibitor AZ505 and renal tubular conditional knockout mice of SMYD2.
Results
Following AKI, the expression levels of SMYD2 and H3K36Me3 were significantly increased, along with the increase of serum creatinine (Scr) and urea nitrogen (BUN) levels, renal tubule cell injury and apoptosis. Administration ofAZ505 further increased levels of Scr and BUN, enhanced the expression of neutrophil gelatinase- associated lipocalin (NGAL) ,kidney damage molecule-1 (Kim1) , and the apoptosis-related proteins such as cysteine-aspartate protease 3 (Caspase3), polyadp ribose transferase (PARP) and BAX. Conversely, pharmacological inhibition of SMYD2 reduced the expression of proliferating cell nuclear antigen and Vimentin. Similarly, conditional knockout of renal tubule SMYD2 aggravated renal impairment, tubular cell injury and apoptosis and inhibited the dedifferentiation and proliferation of renal tubular cells in mice following acute injury. Moreover, AZ505 and tubule conditional SMYD2 knockouts significantly inhibited phosphorylation of renal epidermal growth factor receptor (EGFR), Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) . In cultured renal tubular cells, selective inhibition of SMYD2 by AZ05 or silencing of EGFR by siRNA also resulted in decreased phosphorylation of EGFR, Akt and Erk1/2.
Conclusion
These findings suggest that the expression and activation of endogenous SMYD2 contributes to renal protection and tubular cell regeneration through a mechanism involved in the activation of EGFR signaling pathway.
Funding
- Government Support – Non-U.S.