Pharmacological inhibition of the mixed lineage leukemia 1-menin interaction aggravates acute kidney injury induced by folic acid and ischemia-reperfusion in mice

• Published in: American journal of physiology. Renal physiology 2023-11, Vol.325 (5), p.F669-F680
• Main Authors: Hou, Xiying, Cui, Binbin, Qiu, Andong, Liu, Na, Zhuang, Shougang
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - metabolism; Animal models; Animals; Antigens; Apoptosis; Cell injury; Creatinine; Epidermal growth factor; ErbB Receptors - metabolism; Extracellular signal-regulated kinase; Folic acid; Folic Acid - pharmacology; Gelatinase; Histone H3; Histone methyltransferase; Histones - metabolism; Ischemia; Ischemia - complications; Kidneys; Kinases; Leukemia; Leukemia - complications; Leukemia - drug therapy; Leukocytes (neutrophilic); Lipocalin; Lysine - therapeutic use; Methylation; Methyltransferase; Methyltransferases - metabolism; Mice; Myeloid-Lymphoid Leukemia Protein - adverse effects; Myeloid-Lymphoid Leukemia Protein - metabolism; Phosphorylation; Recovery of function; Renal function; Reperfusion; Reperfusion Injury - complications; Signal transduction; Transcription Factors - metabolism; Vimentin
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00287.2022

Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation (H3K4me3) and partially exerts its untoward functional effects by interacting with multiple subunits including menin and WD repeat-containing protein 5 (WDR5). In this study, we investigated the role and mechanisms of MLL1 in murine models of acute kidney injury induced by folic acid (FA) and ischemia-reperfusion. Injury to the kidney elevated the expression of MLL1, menin, WDR5, and H3K4Me3, which was accompanied by increased serum creatinine and blood urea nitrogen, renal tubular injury, and apoptosis. Pharmacological inhibition of MLL1 activity with MI503 to disrupt the interaction between MLL1 with menin further increased serum creatinine and blood urea nitrogen levels, enhanced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and induced more apoptosis in the kidney following FA and ischemia-reperfusion injury. In contrast, MI503 treatment decreased the expression of vimentin and proliferating cell nuclear antigens. Similarly, treatment with MM102 to disrupt the interaction between MLL1 and WDR5 also worsened renal dysfunction, aggravated tubular cell injury, increased apoptosis, and inhibited cellular dedifferentiation and proliferation in mice following FA injection. Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor, 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 epidermal growth factor receptor signaling pathway. Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation and exerts its functional roles by interacting with multiple subunits. In this study, we demonstrated that inhibition of MLL1 activity by MI503 or MM102 aggravated renal injury and apoptosis and suppressed renal tubular cell dedifferentiation and proliferation, suggesting that MLL1 activation during acute kidney injury acts as an intrinsic protective mechanism to mediate renal tubular cell survival and regeneration.