Angiotensin AT1 receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells

Li Zhou, Hong Xue, Ping Yuan, Jun Ni, Chen Yu, Yu Huang, Li-Min Lu
Clinical and Experimental Pharmacology & Physiology 2010, 37 (9): e152-7
1. Renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT) under hyperglycaemic conditions, which is associated with renal interstitial fibrosis. Activation of the renin-angiotensin system (RAS) is involved in diabetic nephropathy. The present study investigated the positive role of angiotensin AT1 receptors in high glucose-induced EMT in cultured tubular epithelial cells. 2. A rat kidney proximal tubular epithelial cell line (NRK-52E) was used in the present study. Levels of EMT makers, namely E-cadherin and vimentin, were estimated using fluorescence immunocytochemistry, mRNA levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptors were determined by real-time polymerase chain reaction, protein levels of E-cadherin, vimentin, fibronectin, matrix metallopeptidase (MMP)-9 and phosphorylated extracellular signal-regulated kinase (ERK) 1/2 were analysed by western blotting and the concentrations of angiotensin (Ang) II and transforming growth factor (TGF)-beta1 in the culture medium were determined by enzyme immunoassay and ELISA. 3. High glucose (30 mmol/L) induced EMT and increased the synthesis of fibronectin and MMP-9. Furthermore, high glucose increased AGT, ACE and AT(1) receptor mRNA levels, as well as AngII and TGF-beta1 concentrations in the culture medium and ERK1/2 phosphorylation. Pretreatment of cells for 15 min with the AT1 receptor antagonist losartan (10(-5) mol/L) attenuated high glucose-induced increases in TGF-beta1 and ERK1/2 phosphorylation and reduced EMT, as well as the consequent synthesis of fibronectin and MMP-9. 4. The results of the present study suggest that the activated local RAS mediates high glucose-induced EMT. By activating AT1 receptors and stimulating TGF-beta1 synthesis, the elevated local RAS participates in high glucose-induced EMT and increased extracellular matrix secretion.

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