Adrenomedullin Impairs the Profibrotic Effects of Transforming Growth Factor-β1 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-β1 (TGF-β1)-stimulated cell growth, synthesis of extracellular matrix (ECM) components and the related molecular mechanism in a human tubular epithelial cell line HK-2. TGF-β1 inhibited cell proliferation induced by fetal bovine serum, but neither AM itself affectted cell proliferation, nor did AM influence TGF-β1-caused cell growth arrest. However, AM beginning at 10-8 M alleviated the action of TGF-β1-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-β1, AM at 10-8 M exerted no effect on TGF-β1-induced Smad2 phosphorylation, but prevented the suppression of the inhibitory Smad6 protein by TGF-β1 and restored Smad2-Samd6 complex formation. Our results suggest that AM can attenuate TGF-β1-mediated renal tubulointerstitial ECM turnover via an antagonistic mechanism of inhibitory Smad in TGF-β1-elicited signaling.