Involvement of ADAM17-Klotho Crosstalk in High Glucose-Induced Alterations of Podocyte Function

Area of Science:

• Nephrology
• Diabetology
• Molecular Biology

Background:

• Diabetic kidney disease (DKD) is characterized by microalbuminuria, linked to podocyte injury and oxidative stress from high glucose (HG).
• Klotho protein, crucial for podocyte health, is reduced under HG conditions.
• ADAM17 (a disintegrin and metalloproteinase 17) mediates Klotho shedding from cell membranes.

Purpose of the Study:

• To investigate the role of ADAM17 in the HG-induced decrease of Klotho in human podocytes.
• To elucidate the mechanism linking HG, ADAM17, Klotho, and podocyte dysfunction.

Main Methods:

• Cultured human podocytes exposed to high glucose conditions.
• Measured ADAM17 protein levels, extracellular activity, and NADPH oxidase activity.
• Assessed glomerular albumin permeability and Klotho expression.
• Utilized ADAM17 inhibitors and gene silencing techniques.
• Administered Klotho to assess protective effects.

Main Results:

• HG significantly increased ADAM17 protein and extracellular activity in podocytes, correlating with increased albumin permeability.
• HG-induced podocyte dysfunction, oxidative stress, and albuminuria were reversed by ADAM17 inhibition or Klotho supplementation.
• Downregulation of Klotho expression led to elevated extracellular ADAM17 activity.

Conclusions:

• Hyperglycemia exacerbates podocyte dysfunction through ADAM17 activation, leading to Klotho shedding.
• Klotho protects podocyte function in hyperglycemia via an ADAM17-dependent mechanism.
• Targeting the ADAM17-Klotho axis offers a potential therapeutic strategy for diabetic kidney disease.