1. Academic Validation
  2. NSD2 modulates Drp1-mediated mitochondrial fission in chronic renal allograft interstitial fibrosis by methylating STAT1

NSD2 modulates Drp1-mediated mitochondrial fission in chronic renal allograft interstitial fibrosis by methylating STAT1

  • Pharmacol Res. 2024 Jan 6:200:107051. doi: 10.1016/j.phrs.2023.107051.
Jianjian Zhang 1 Weibin Xie 2 Bin Ni 3 Zhuohang Li 2 Dengyuan Feng 1 Yao Zhang 1 Qianguang Han 1 Hai Zhou 3 Min Gu 3 Ruoyun Tan 4
Affiliations

Affiliations

  • 1 Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
  • 2 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 4 Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China. Electronic address: tanruoyun112@vip.sina.com.
Abstract

Renal interstitial fibrosis/tubular atrophy (IF/TA) is a prominent pathological feature of chronic allograft dysfunction (CAD). Our previous study has demonstrated that epithelial-mesenchymal transition (EMT) plays a significant role in shaping the development of IF/TA. Nuclear SET domain (NSD2), a Histone Methyltransferase catalyzing methylation at lysine 36 of histone 3, is crucially involved in the development and progression of solid tumors. But its role in the development of renal allograft interstitial fibrosis has yet to be elucidated. Here, we characterize NSD2 as a crucial mediator in the mouse renal transplantation model in vivo and a model of tumor necrosis factor-α (TNF-α) stimulated-human renal tubular epithelial cells (HK-2) in vitro. Functionally, NSD2 knockdown inhibits EMT, dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in mice. Conversely, NSD2 overexpression exacerbates fibrosis-associated phenotypes and mitochondrial fission in tubular cells. Mechanistically, tubular NSD2 aggravated the Drp-1 mediated mitochondrial fission via STAT1/ERK/PI3K/Akt signaling pathway in TNF-α-induced epithelial cell models. Momentously, mass spectrometry (MS) Analysis and site-directed mutagenesis assays revealed that NSD2 interacted with and induced Mono-methylation of STAT1 on K173, leading to its phosphorylation, IMB1-dependent nuclear translocation and subsequent influence on TNF-α-induced EMT and mitochondrial fission in NSD2-dependent manner. Collectively, these findings shed LIGHT on the mechanisms and suggest that targeting NSD2 could be a promising therapeutic approach to enhance tubular cell survival and alleviate interstitial fibrosis in renal allografts during CAD.

Keywords

Chronic allograft dysfunction; Epithelial-mesenchymal transition; Mitochondrial fission; NSD2; Renal interstitial fibrosis/tubular atrophy; STAT1.

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