High-glucose and advanced glycosylation end products increased podocyte permeability via PI3-K/Akt signaling

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2010-04, Vol.88 (4), p.391-400
• Main Author: Ha, Tae-Sun
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; Epithelial Cells - metabolism; Etiopathogenesis. Screening. Investigations. Target tissue resistance; General aspects; Glucose - metabolism; Glycation End Products, Advanced - metabolism; Human Genetics; Internal Medicine; Kidneys; Medical sciences; Membrane Proteins - metabolism; Mice; Microscopy, Confocal - methods; Models, Biological; Molecular Medicine; Nephrology. Urinary tract diseases; Original Article; Permeability; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Podocytes - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction; Urinary system involvement in other diseases. Miscellaneous; Zonula Occludens-1 Protein
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-009-0575-8

Regardless of the underlying disease, the proteinuric condition demonstrates ultrastructural changes in podocytes with retraction and effacement of the highly specialized interdigitating foot processes. To investigate how high-glucose (HG) and advanced glycosylation end products (AGE) induce podocyte phenotypical changes, including quantitative and distributional changes of zonula occludens (ZO)-1 protein and search for the signaling mechanisms, we cultured rat glomerular epithelial cells (GEpC) and mouse podocytes under: (1) normal glucose (5 mM, control); (2) HG (30 mM); (3) AGE-added; or (4) HG plus AGE-added conditions. HG plus AGE increased the permeability of monolayered GEpCs and induced ultrastructural separation between confluent GEpCs. ZO-1 moved to inner actin filament complexes in both AGE- and/or HG by confocal imaging. HG plus AGE-added condition also decreased ZO-1 protein amount and mRNA expression compared to normal glucose or osmotic control conditions. We could also confirm the induction of RAGE (receptor for AGE) and PI3-K/Akt signaling pathway by AGE and HG. In addition, LY294002, a PI3-K inhibitor, could prevent the quantitative and distributional changes of ZO-1 and RAGE and the increased permeability induced by HG and AGE. These findings suggest that diabetic conditions induce the podocyte ZO-1 changes via RAGE and PI3-K/Akt signaling, leading to increased permeability.