The PKM2 activator TEPP‐46 suppresses kidney fibrosis via inhibition of the EMT program and aberrant glycolysis associated with suppression of HIF‐1α accumulation

DOI Web Site Web Site PubMed 6 Citations 34 References Open Access
  • Haijie Liu
    Department of Diabetology and Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan
  • Yuta Takagaki
    Department of Diabetology and Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan
  • Asako Kumagai
    Department of Diabetology and Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan
  • Keizo Kanasaki
    Department of Diabetology and Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan
  • Daisuke Koya
    Department of Diabetology and Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan

Description

<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims/Introduction</jats:title><jats:p>Tubulointerstitial fibrosis is a hallmark of diabetic nephropathy and is associated with an epithelial‐to‐mesenchymal transition (EMT) program and aberrant glycolysis. Dimeric pyruvate kinase (PK) M2 (PKM2) acts as a key protein kinase in aberrant glycolysis by promoting the accumulation of hypoxia‐inducible factor (HIF)‐1α, while tetrameric PKM2 functions as a pyruvate kinase in oxidative phosphorylation. The aim of the research is to study the effect of PKM2 tetramer activation on preventing kidney fibrosis via suppression of aberrant glycolysis and the EMT program.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p><jats:italic>In vivo</jats:italic>: Streptozotocin (STZ) was utilized to induce diabetes in 8‐week‐old CD‐1 mice; 4 weeks after diabetes induction, proteinuria‐induced kidney fibrosis was developed by intraperitoneal injection of bovine serum albumin (BSA: 0.3 g/30 g BW) for 14 days; The PKM2 activator TEPP‐46 was also administered orally simultaneously. <jats:italic>In vitro</jats:italic>: HK2 cells were co‐treated with high‐glucose media or/and TGF‐β1 and TEPP46 for 48 h, cellular protein was extracted for evaluation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Diabetic mice developed kidney fibrosis associated with aberrant glycolysis and EMT; BSA injection accelerated kidney fibrosis in both the control and diabetic mice; TEPP‐46 rescued the kidney fibrosis. In HK2 cells, TEPP‐46 suppressed the EMT program induced by TGF‐β1 and/or high‐glucose incubation. TEPP‐46‐induced PKM2 tetramer formation and PK activity resulted in suppression of HIF‐1α and lactate accumulation. Specific siRNA‐mediated knockdown of HIF‐1α expression diminished high glucose‐induced mesenchymal protein levels.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>PKM2 activation could restore the tubular phenotype via suppression of the EMT program and aberrant glycolysis, providing an alternative target to mitigate fibrosis in diabetic kidneys.</jats:p></jats:sec>

Journal

Citations (6)*help

See more

References(34)*help

See more

Related Projects

See more

Keywords

Details 詳細情報について

Report a problem

Back to top