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Imidazopyrimidine-based pyruvate kinase M2 activator halts diabetic nephropathy progression via modulating

Meenakshi Jain1, Adil Ali Sayyed2, Piyush Gondaliya1

  • 1Department of Biotechnology, National Institute of Pharmaceutical Education and Research- Ahmedabad, Gandhinagar, Gujarat, 382355, India.

Chemico-Biological Interactions
|July 27, 2025
PubMed

Insights

A novel compound, 15n, activates pyruvate kinase M2 (PKM2) tetramers, protecting against diabetic nephropathy (DN) progression. This PKM2 activator reduced kidney fibrosis and dysfunction in preclinical models, offering a potential therapeutic strategy for DN.

Area of Science:

  • Biochemistry
  • Nephrology
  • Pharmacology

Background:

  • Diabetic nephropathy (DN) affects 40% of diabetic patients, causing kidney damage via metabolic dysregulation and toxic glucose metabolite accumulation.
  • Upregulated pyruvate kinase M2 (PKM2) promotes glycolysis, hypoxia-inducible factor-1 (HIF-1) activation, and epithelial-to-mesenchymal transition (EMT), contributing to renal fibrosis and dysfunction in DN.
  • PKM2's tetrameric form protects against DN, while its dimeric form amplifies inflammation. Pharmacological activation of PKM2 tetramers shows promise in preclinical models.

Purpose of the Study:

  • To evaluate the efficacy of a novel imidazopyrimidine-based derivative, 15n, as a PKM2 activator in preclinical models of diabetic nephropathy.
  • To investigate 15n's effects on PKM2 tetramer expression, EMT, fibrosis, and renal function in vitro and in vivo.

Main Methods:

  • In vitro study using diabetic nephropathy-induced human renal proximal tubular epithelial cells (hRPTEC).
  • In vivo study using a Streptozotocin-induced diabetic nephropathy mouse model.
  • Assessment of PKM2 tetramer expression, EMT markers, fibrosis, and renal function (serum urea and creatinine levels).

Main Results:

  • 15n treatment (10 μM) increased PKM2 tetramer expression in DN-induced hRPTEC cells.
  • 15n treatment reduced EMT and fibrosis progression in vitro.
  • Histological analysis and serum marker evaluation in the mouse model showed attenuated DN progression and decreased urea and creatinine levels in the 15n-treated group.

Conclusions:

  • The novel PKM2 activator 15n demonstrates significant renal protective effects in preclinical models of diabetic nephropathy.
  • 15n likely confers protection by modulating the epithelial-to-mesenchymal transition pathway and restoring metabolic balance.
  • Targeting PKM2 tetramer activation represents a promising therapeutic strategy for preventing fibrotic kidney disease in diabetic nephropathy.
Keywords:
DiabetesEpithelial-to-mesenchymal transitionFibrosisHyperglycaemiaHypoxia-inducible factor-1

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