| 20015942 |
Lee YJ, Han HJ: Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3{beta}, Snail1, and {beta}-catenin in renal proximal tubule cells. Am J Physiol Renal Physiol. 2009 Dec 16.
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists ameliorate renal fibrotic lesions in diabetic nephropathy. However, the effects of the agonists on epithelial-mesenchymal transition (EMT) linked to membrane transport dysfunction are unknown. The present study aimed to verify the effects of the PPARgamma agonist troglitazone on high glucose (HG)-induced EMT in primary cultured renal proximal tubular epithelial cells (PTCs). HG (25 mM) as well as hydrogen peroxide (H2O2) and transforming growth factor-beta1 (TGF-beta1) decreased expression of epithelial cell marker E-cadherin and increased the expression of the mesenchymal markers vimentin and alpha-smooth muscle actin (alpha-SMA). HG, H2O2, and TGF-beta1 decreased Na (+)/H (+) exchangers (NHEs) or Na (+)/glucose cotransporters (SGLTs) and glucose uptake, showing the membrane transport dysfunction. HG stimulated the production of cellular reactive oxygen species (ROS) and antioxidant blocked HG-induced increase in phosphatidylinositol 3-kinase (PI3K)/Akt activation. Antioxidants and inhibitors of PI3K/Akt reversed the HG-induced EMT protein expressions. Inhibition of PI3K/Akt also blocked HG-induced glycogen synthase kinase-3beta (GSK-3beta) phosphorylation. HG and lithium chloride (GSK-3beta inhibitor) blocked Snail1 and beta-catenin activation. Moreover, transfection with snail1 or beta-catenin small interfering RNA (siRNA) reversed HG-induced EMT protein expressions. Importantly, HG decreased PPARgamma activation and troglitazone reversed HG-induced expressions of PI3K/Akt, GSK-3beta, Snail1, and beta-catenin as well as EMT proteins. Finally, inhibitors of PI3K/Akt, snail1/beta-catenin siRNA, and troglitazone blocking the HG-induced EMT restored glucose uptake in PTCs. In conclusion, HG induces EMT through ROS, PI3K/Akt, GSK-3beta, snail, and beta-catenin. Subsequently, HG-induced EMT may result in SGLT dysfunction that is restored by the PPARgamma agonist troglitazone in primary cultured PTCs. Key words: High glucose (HG), epithelial-mesenchymal transition (EMT), peroxisome proliferator-activated receptor gamma agonist, glucose uptake. |
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