Ezrin contributes to impaired podocyte migration and adhesion caused by advanced glycation end products

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Abstract
Aim: Podocytes are specialized epithelial cells that play a critical role in the glomerular filtration barrier. Podocyte abnormalities are linked to increasing albuminuria and progression to end‐stage renal failure as observed in diabetic nephropathy. Advanced glycation end products (AGEs) have been strongly linked to the development of diabetic nephropathy, and we have previously shown that AGEs inhibit ezrin actions in proximal tubule cells. As ezrin plays a key role in controlling podocyte foot process integrity, the present study investigated the contribution of ezrin to AGE‐induced podocyte damage.Methods: Conditionally immortalized human podocytes were cultured with or without AGEs, and changes in morphology, protein expression and cell function were analyzed.Results: Fully differentiated podocytes had long finger‐like protrusions forming slit diaphragm structures. Immunofluorescence showed ezrin is mainly localized to the cell membrane with intense fluorescence on cellular protrusions. After AGE‐BSA treatment for 6 days, podocytes were rounder with fewer protrusions. Western blotting showed a time‐dependent reduction in ezrin levels compared with BSA‐treated cells. AGE‐BSA treatment reduced podocyte adhesion to fibronectin and inhibited migration. Overexpression of ezrin completely reversed AGE‐BSA inhibition of podocyte adhesion to fibronectin and partially reversed AGE‐induced inhibition of migration.Conclusion: These results show a role for ezrin in AGE‐induced podocyte damage and suggest a new avenue for possible therapeutic intervention in diabetic nephropathy.
Funding Information
  • Diabetes Australia Research Trust

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