Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells.
Adrenomedullin (AM) was originally identified as a vasodilator peptide, and has recently been shown to be an antiproliferative factor in renal mesangial cells, suggesting that adrenomedullin may impair the progression of glomerulosclerosis. This study was to investigate the effect of adrenomedullin on transforming growth factor-beta1 (TGF-beta1)-stimulated cell growth, synthesis of extracellular matrix (ECM) components and the related molecular mechanism in a human tubular epithelial cell line HK-2. TGF-beta1 inhibited cell proliferation induced by fetal bovine serum, but neither AM itself affectted cell proliferation, nor did AM influence TGF-beta1-caused cell growth arrest. However, AM beginning at 10(-8) M alleviated the action of TGF-beta1-stimulated cellular collagen synthesis and secretion of fibronectin into cell culture supernatant. Activation of Smad proteins is known to be the key signaling pathway of the profibrotic effect of TGF-beta1, AM at 10(-8) M exerted no effect on TGF-beta1-induced Smad2 phosphorylation, but prevented the suppression of the inhibitory Smad6 protein by TGF-beta1 and restored Smad2-Samd6 complex formation. Our results suggest that AM can attenuate TGF-beta1-mediated renal tubulointerstitial ECM turnover via an antagonistic mechanism of inhibitory Smad in TGF-beta1-elicited signaling.
Huang
Haichang
H
Division of Nephrology, Peking University First Hospital and Institute of Nephrology, China.
Ma
Chunyan
C
Yang
Min
M
Tang
Chaoshu
C
Wang
Haiyan
H
D053607:Adrenomedullin; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051899:Smad2 Protein; D051905:Smad6 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D046912:Multiprotein Complexes; D010455:Peptides; C497782:SMAD2 protein, human; C497802:SMAD6 protein, human; D051899:Smad2 Protein; D051905:Smad6 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053607:Adrenomedullin