MLL1 Activation Contributes to Renal Protection and Regeneration Following AKI Induced by Folic Acid and Ischemia/Reperfusion
- 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
- Hou, Xiying, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Zhuang, Shougang, Department of Medicine, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States
Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation (H3K4me3) and exerts its functional roles by interacting with multiple subunits including WD repeat-containing protein 5 (WDR5) and Menin. In this study, we investigated the role and mechanisms of MLL1 in murine models of acute kidney injury (AKI) induced by folic acid (FA) and ischemia/reperfusion (I/R).
A folic acid (FA)-induced AKI murine model was created by peritoneal injection of FA at 250 mg/kg and a biliteral I/R murine models were established by occluding with a non- traumatic vascular clamp for 35 minutes in mice.
Injury to the kidney elevated expression of MLL1, Menin, WDR5 and H3K4Me3, which was accompanied by increased serum creatine (Scr) and blood urea nitrogen (BUN), renal tubular injury and apoptosis. Pharmacological inhibition of MLL1 activity with MI503 to disrupt the interaction between MLL1 with Menin further increased Scr and BUN levels, enhanced expression of neutrophil gelatinase associated lipocalin and kidney injury molecule-1, and induced more apoptosis in the kidney following FA and I/R injury. In contrast, MI503 decreased the expression of vimentin and proliferating cell nuclear antigen. Similarly, treatment with MM102 to disrupt the interaction between MLL1 and WDR5 also worsened renal dysfunction, aggravated tubular cell injury and apoptosis, and inhibited cellular dedifferentiation and proliferation in mice following FA injection. Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 and extracellular signal-regulated kinase-1/2 in injured kidneys.
Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the EGFR signaling pathway.
- Government Support – Non-U.S.