Akt activation and augmented fibronectin production in hyperhexosemia

Area of Science:

• Biochemistry
• Molecular Biology
• Diabetology

Background:

• Diabetes-associated dysmetabolism can elevate extracellular matrix (ECM) protein synthesis.
• Glucose-induced fibronectin (FN) production is regulated by protein kinase B (PKB, also known as Akt).

Purpose of the Study:

• To investigate the role of Akt1 in ECM protein production in organs affected by diabetic complications.
• To elucidate the mechanism linking hyperhexosemia, Akt activation, and ECM synthesis.

Main Methods:

• Utilized Akt1/PKBalpha knockout mice and wild-type littermates.
• Induced hyperhexosemia using 8-week galactose feeding to avoid insulin effects.
• Assessed fibronectin (FN), EDB(+)FN, TGF-beta mRNA, Akt phosphorylation, kinase activity, and NF-kappaB/AP-1 activation in retina, heart, and kidney.

Main Results:

• Galactose feeding upregulated FN, EDB(+)FN, and TGF-beta in wild-type mice, causing ECM deposition in renal and cardiac tissues.
• These effects were prevented in Akt1-deficient mice.
• Hyperhexosemia activated NF-kappaB and AP-1 in wild-type mice, an effect abolished in Akt1 knockout mice.

Conclusions:

• Hyperhexosemia-induced Akt/PKB activation is a key mechanism driving NF-kappaB and AP-1 activation.
• This pathway leads to increased ECM protein synthesis in organs affected by diabetic complications.
• Targeting Akt/PKB signaling may offer a strategy to mitigate diabetic organ damage.