2. Academic Validation
  3. Lactate drives epithelial-mesenchymal transition in diabetic kidney disease via the H3K14la/KLF5 pathway

Lactate drives epithelial-mesenchymal transition in diabetic kidney disease via the H3K14la/KLF5 pathway

  • Redox Biol. 2024 Jun 20:75:103246. doi: 10.1016/j.redox.2024.103246.
Xuanxuan Zhang 1,  Jicong Chen 1,  Ruohui Lin 1,  Yaping Huang 1,  Ziyuan Wang 1,  Susu Xu 2,  Lei Wang 1,  Fang Chen 3,  Jian Zhang 4,  Ke Pan 5,  Zhiqi Yin 6
Affiliations

Affiliations

  • 1 School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjin, 211200, China.
  • 3 Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.
  • 4 Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjin, 211200, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. Electronic address: zhangjian@jsatcm.com.
  • 5 School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: kpan@cpu.edu.cn.
  • 6 School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: cpu-yzq@cpu.edu.cn.
PMID: 38925041 DOI: 10.1016/j.redox.2024.103246
Abstract

High levels of urinary lactate are an increased risk of progression in patients with diabetic kidney disease (DKD). However, it is still unveiled how lactate drive DKD. Epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial cells polarity and cell-cell adhesion, and the acquisition of mesenchymal-like phenotypes, is widely recognized a critical contributor to DKD. Here, we found a switch from Oxidative Phosphorylation (OXPHOS) toward glycolysis in AGEs-induced renal tubular epithelial cells, thus leading to elevated levels of renal lactic acid. We demonstrated that reducing the lactate levels markedly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanically, we observed lactate increased the levels of histone H3 lysine 14 lactylation (H3K14la) in DKD. ChIP-seq & RNA-seq results showed histone lactylation contributed to EMT process by facilitating KLF5 expression. Moreover, KLF5 recognized the promotor of cdh1 and inhibited its transcription, which accelerated EMT of DKD. Additionally, nephro-specific knockdown and pharmacological inhibition of KLF5 diminished EMT development and attenuated DKD fibrosis. Thus, our study provides better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD by disruption of the lactate-drived H3K14la/KLF5 pathway.

Keywords

Diabetic kidney disease; Epithelial-mesenchymal transition; Glycolysis; KLF5; Lactate.

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