| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Departments of Medicine-Nephrology,* Baylor College of Medicine, Houston, Texas; the Department of Medicine, Austin and Repatriation Medical Center, The University of Melbourne, Melbourne, Australia; and the Division of Surgical Science, College of Physicians & Surgeons, Department of Surgery, Columbia University, New York, New York
Advanced glycation end products (AGEs) have been shown to play a role in tubular epithelial-myofibroblast transdifferentiation (TEMT) in diabetic nephropathy, but the intracellular signaling pathway remains unknown. We report here that AGEs signal through the receptor for AGEs (RAGE) to induce TEMT, as determined by de novo expression of a mesenchymal marker (
-smooth muscle actin, -SMA) and loss of epithelial marker (E-cadherin), directly through the MEK1-ERK1/2 MAP kinase pathway, which is TGF-ß independent. This is supported by the following findings: AGEs induced de novo -SMA mRNA expression as early as 2 hours followed by a loss of E-cadherin before TGF-ß mRNA expression at 24 hours and occurred in the absence of TGF-ß and AGE-induced activation of ERK1/2 MAP kinase at 15 minutes and TEMT at 24 hours were completely blocked by a neutralizing RAGE antibody, a soluble RAGE receptor, an ERK1/2 MAP kinase inhibitor (PD98059), and DN-MEK1, but not by a neutralizing TGF-ß antibody. Thus, this study demonstrates that AGEs activate the RAGE-ERK1/2 MAP kinase pathway to mediate the early TEMT process. The findings from this study suggest that targeting the RAGE or the ERK MAP kinase pathway may provide new therapeutic strategies for diabetic nephropathy and shed new light on the pathogenesis of diabetic nephropathy.
This article has been cited by other articles:
 |
|
 |
|
  A. C.K. Chung, H. Zhang, Y.-Z. Kong, J.-J. Tan, X. R. Huang, J. B. Kopp, and H. Y. Lan Advanced Glycation End-Products Induce Tubular CTGF via TGF-{beta}-Independent Smad3 Signaling J. Am. Soc. Nephrol., February 1, 2010; 21(2): 249 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis J. Am. Soc. Nephrol., February 1, 2010; 21(2): 212 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wu, C. Mei, H. Vlassara, G. E. Striker, and F. Zheng Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells Am J Physiol Renal Physiol, December 1, 2009; 297(6): F1622 - F1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. An, H. J. Kim, K.-H. Cho, and N. D. Vaziri Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney Am J Physiol Renal Physiol, October 1, 2009; 297(4): F895 - F903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cheng, W. Zhou, G. M. Warner, B. E. Knudsen, V. D. Garovic, C. E. Gray, L. O. Lerman, J. L. Platt, J. C. Romero, S. C. Textor, et al. Temporal analysis of signaling pathways activated in a murine model of two-kidney, one-clip hypertension Am J Physiol Renal Physiol, October 1, 2009; 297(4): F1055 - F1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nakao, G. Faleo, M. A. Nalesnik, J. Seda-Neto, J. Kohmoto, and N. Murase Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function Am J Physiol Renal Physiol, July 1, 2009; 297(1): F19 - F26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Fedorova, V. Raju, N. El-Okdi, A. Shidyak, D. J. Kennedy, S. Vetteth, D. R. Giovannucci, A. Y. Bagrov, O. V. Fedorova, J. I. Shapiro, et al. The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition Am J Physiol Renal Physiol, April 1, 2009; 296(4): F922 - F934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Radisky and J. A. Przybylo Matrix Metalloproteinase-induced Fibrosis and Malignancy in Breast and Lung Proceedings of the ATS, April 15, 2008; 5(3): 316 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Englert, L. E. Hanford, N. Kaminski, J. M. Tobolewski, R. J. Tan, C. L. Fattman, L. Ramsgaard, T. J. Richards, I. Loutaev, P. P. Nawroth, et al. A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis Am. J. Pathol., March 1, 2008; 172(3): 583 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kumano-Kuramochi, Q. Xie, Y. Sakakibara, S. Niimi, K. Sekizawa, S. Komba, and S. Machida Expression and Characterization of Recombinant C-Terminal Biotinylated Extracellular Domain of Human Receptor for Advanced Glycation End Products (hsRAGE) in Escherichia coli J. Biochem., February 1, 2008; 143(2): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. He, H. Kubo, K. Ishizawa, A. E. Hegab, Y. Yamamoto, H. Yamamoto, and M. Yamaya The role of the receptor for advanced glycation end-products in lung fibrosis Am J Physiol Lung Cell Mol Physiol, December 1, 2007; 293(6): L1427 - L1436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zhang, Z. Jia, X. Guo, and T. Yang Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin Am J Physiol Renal Physiol, September 1, 2007; 293(3): F723 - F731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Uribarri and K. R. Tuttle Advanced Glycation End Products and Nephrotoxicity of High-Protein Diets Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1293 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. C. Burns, S. M. Twigg, J. M. Forbes, J. Pete, C. Tikellis, V. Thallas-Bonke, M. C. Thomas, M. E. Cooper, and P. Kantharidis Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product-Induced Tubular Epithelial-to-Mesenchymal Transition: Implications for Diabetic Renal Disease J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2484 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. G. Docherty, O. E. O'Sullivan, D. A. Healy, M. Murphy, A. J. O'Neill, J. M. Fitzpatrick, and R. W. G. Watson TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1202 - F1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Koka, W. Wang, X. R. Huang, S. Kim-Mitsuyama, L. D. Truong, and H. Y. Lan Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II-Generating Pathway in Diabetic Complications Circulation, March 14, 2006; 113(10): 1353 - 1360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Bohlender, S. Franke, G. Stein, and G. Wolf Advanced glycation end products and the kidney Am J Physiol Renal Physiol, October 1, 2005; 289(4): F645 - F659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Huang, L.-Y. Chuang, J.-Y. Guh, C.-J. Chen, Y.-L. Yang, T.-A. Chiang, M.-Y. Hung, and T.-N. Liao Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product-Induced Proliferation in Renal Fibroblasts J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2318 - 2329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Hou, W. Wang, X. R. Huang, P. Fu, T.-H. Chen, D. Sheikh-Hamad, and H. Y. Lan Ultrasound-Microbubble-Mediated Gene Transfer of Inducible Smad7 Blocks Transforming Growth Factor-{beta} Signaling and Fibrosis in Rat Remnant Kidney Am. J. Pathol., March 1, 2005; 166(3): 761 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Y. Rhyu, Y. Yang, H. Ha, G. T. Lee, J. S. Song, S.-t. Uh, and H. B. Lee Role of Reactive Oxygen Species in TGF-{beta}1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells J. Am. Soc. Nephrol., March 1, 2005; 16(3): 667 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Breyer, E. Bottinger, F. C. Brosius III, T. M. Coffman, R. C. Harris, C. W. Heilig, K. Sharma, and for the AMDCC Mouse Models of Diabetic Nephropathy J. Am. Soc. Nephrol., January 1, 2005; 16(1): 27 - 45. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
