High-glucose and advanced glycosylation end products increased podocyte permeability via PI3-K/Akt signaling.
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.
Ha
Tae-Sun
TS
Department of Pediatrics, College of Medicine, Chungbuk National University, Gaeshin-dong 48, Heungdeok-gu, Cheongju, Chungbuk, 361-240, Korea. tsha@chungbuk.ac.kr
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D010539:Permeability; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D008565:Membrane Proteins; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose