Advanced glycation end products induce tubular epithelial-myofibroblast transition through the RAGE-ERK1/2 MAP kinase signaling pathway.
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 (alpha-smooth muscle actin, alpha-SMA) and loss of epithelial marker (E-cadherin), directly through the MEK1-ERK1/2 MAP kinase pathway, which is TGF-beta independent. This is supported by the following findings: AGEs induced de novo alpha-SMA mRNA expression as early as 2 hours followed by a loss of E-cadherin before TGF-beta mRNA expression at 24 hours and occurred in the absence of TGF-beta 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-beta 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.
Li
Jin H
JH
Departments of Medicine-Nephrology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wang
Wansheng
W
Huang
Xiao R
XR
Oldfield
Matthew
M
Schmidt
Ann M
AM
Cooper
Mark E
ME
Lan
Hui Y
HY
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D000199:Actins; D015820:Cadherins; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic