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Empagliflozin, Linagliptin, and Metformin Differentially Affect Renal PI3K/Akt and MAPK/ERK Signaling Pathways in

Anton I Korbut1, Elizaveta A Ananishnikova1, Nikolai B Orlov1

  • 1Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL-Branch of IC&G SB RAS), Novosibirsk 630117, Russia.

International Journal of Molecular Sciences
|July 28, 2026
PubMed

Insights

Diabetic kidney disease involves cell cycle, autophagy, and apoptosis dysregulation. Anti-diabetic drugs like empagliflozin, linagliptin, and metformin modulate key signaling pathways, potentially offering renal protection.

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic kidney disease (DKD) is linked to cell cycle, autophagy, and apoptosis dysregulation.
  • The PI3K/Akt and MAPK/ERK signaling pathways are implicated in DKD pathogenesis.
  • Understanding these pathways is crucial for developing renoprotective strategies.

Purpose of the Study:

  • To investigate the role of PI3K/Akt and MAPK/ERK pathway mediators in the kidneys of type 2 diabetic mice (db/db).
  • To evaluate the effects of empagliflozin (SGLT2 inhibitor), linagliptin (DPP4 inhibitor), and metformin on these pathways.
  • To elucidate the mechanisms underlying DKD and the renal protective effects of these anti-diabetic agents.

Main Methods:

  • Utilized db/db mice, a model for type 2 diabetes, treated with empagliflozin, linagliptin, or metformin for 8 weeks.
  • Assessed AMPKα1 and PI3Kp110β levels in renal cortex and medulla via Western Blot.
  • Analyzed phosphorylated signaling molecules using multiplex analysis.

Main Results:

  • Db/db mice exhibited altered levels of PI3Kp110β, phospho-PTEN, HSP27, MEK1, BAD, and phospho-rpS6.
  • Empagliflozin normalized cortical PI3Kp110β, phospho-MEK1, and medullar phospho-PTEN.
  • Linagliptin restored PI3Kp110β, while metformin upregulated AMPKα1, PI3Kp110β, phospho-GSK-3α/β, MEK1, and phospho-HSP27.

Conclusions:

  • The study reveals specific alterations in PI3K/Akt and MAPK/ERK signaling in DKD.
  • Empagliflozin, linagliptin, and metformin differentially modulate these pathways, contributing to renal protection.
  • Findings offer insights into DKD mechanisms and the renoprotective actions of anti-diabetic medications.
Keywords:
MAPK/ERK signalingPI3K/Akt signalingchronic kidney diseaseempagliflozinlinagliptinmetformintype 2 diabetes

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