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

Accumulating data indicate a role for the dysregulation of the cell cycle, autophagy and apoptosis in diabetic kidney disease. We aimed to evaluate the mediators of the PI3K/Akt and MAPK/ERK signaling pathways in the kidney of db/db mice, a model of type 2 diabetes, treated by the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and metformin. Eight-week-old male db/db mice were randomly assigned to treatment by these agents or vehicle for 8 weeks. Age-matched db/+ mice acted as controls. AMPKα1 and PI3Kp110β were evaluated in the renal cortex and medulla by Western Blot. Phosphorylated forms of principal molecules involved in the PI3K/Akt and MAPK/ERK pathways were assessed by multiplex analysis. Db/db mice had decreased PI3Kp110β, increased phospho-PTEN, HSP27 and MEK1 in the renal cortex and medulla, BAD in the renal cortex and decreased phospho-rpS6 in the renal medulla. Empagliflozin prevented the changes in the levels of cortical PI3Kp110β, phospho-MEK1, and medullar phospho-PTEN. Linagliptin restored PI3Kp110β levels. Both agents further decreased medullar phospho-rpS6. Metformin upregulated cortical AMPKα1, medullar PI3Kp110β, phospho-GSK-3α/β and MEK1, and increased phospho-HSP27 in the renal cortex and medulla. The data may provide further explanation of the mechanism underlying the development of diabetic kidney disease, as well as the renal protective effect of anti-diabetic agents.