1. Academic Validation
  2. Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy

Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy

  • FASEB J. 2023 Jan;37(1):e22712. doi: 10.1096/fj.202100634RRR.
Jianan Zou 1 2 Chao Yu 3 Chunyun Zhang 1 Yingjie Guan 1 Yunhe Zhang 1 Evelyn Tolbert 1 Wei Zhang 1 Ting Zhao 4 George Bayliss 1 Xiaogang Li 5 Zhibin Ye 2 Shougang Zhuang 1 3
Affiliations

Affiliations

  • 1 Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
  • 2 Department of Nephrology, Huadong Hospital, Fudan University, Shanghai, China.
  • 3 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Department of Surgery, Rhode Island Hospital, Brown University, Providence, Rhode Island, USA.
  • 5 Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Abstract

Mixed lineage leukemia 1 (MLL1), a histone H3 lysine 4 (H3K4) methyltransferase, exerts its enzymatic activity by interacting with menin and other proteins. It is unclear whether inhibition of the MLL1-menin interaction influences epithelial-mesenchymal transition (EMT), renal fibroblast activation, and renal fibrosis. In this study, we investigated the effect of disrupting MLL1-menin interaction on those events and mechanisms involved in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), in cultured mouse proximal tubular cells and renal interstitial fibroblasts. Injury to the kidney increased the expression of MLL1 and menin and H3K4 monomethylation (H3K4me1); MLL1 and menin were expressed in renal epithelial cells and renal interstitial fibroblasts. Inhibition of the MLL1-menin interaction by MI-503 administration or siRNA-mediated silencing of MLL1 attenuated UUO-induced renal fibrosis, and reduced expression of α-smooth muscle actin (α-SMA) and fibronectin. These treatments also inhibited UUO-induced expression of transcription factors Snail and Twist and transforming growth factor β1 (TGF-β1) while expression of E-cadherin was preserved. Moreover, treatment with MI-503 and transfection with either MLL siRNA or menin siRNA inhibited TGF-β1-induced upregulation of α-SMA, fibronectin and Snail, phosphorylation of SMAD3 and Akt, and downregulation of E-cadherin in cultured renal epithelial cells. Finally, MI-503 was effective in abrogating serum or TGFβ1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1-menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation.

Keywords

epithelial-mesenchymal transition; menin; mixed lineage leukemia 1; renal fibrosis; renal interstitial fibroblasts.

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