Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2
Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2
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DOI：
10.1096/fj.08-120857
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Samuel, Chrishan S.
中科院分区：
文献类型：
--
作者：
Mookerjee, Ishanee;Hewitson, Tim D.;Samuel, Chrishan S.
激素松弛素通过干扰转化生长因子-β1/Smad2信号通路抑制肾成纤维细胞分化。然而，松弛素-转化生长因子-β1/Smad2相互作用的途径仍不清楚。本研究通过检测人基因-2(H2)松弛蛋白对成纤维细胞和损伤大鼠肾脏成纤维细胞的影响，探讨其在体外调控肌成纤维细胞分化的信号机制。用含有60-70%的肌成纤维细胞的培养细胞来确定哪些松弛素受体、G蛋白和信号通路参与了H2松弛素介导的α-平滑肌肌动蛋白(α-SMA；肌成纤维细胞分化的标志)的调节。H2松弛素仅在松弛素家族多肽受体1(RXFP1)存在的情况下抑制α-SMA免疫染色和胶原浓度。H_2松弛素能在G(I/O)抑制的情况下引起cAMP的一过性升高，并持续增加细胞外信号调节激酶(ERK)-1/2的磷酸化。此外，抑制神经元型一氧化氮合酶、NO和cGMP可显著阻断松弛素对α-SMA和Smad2磷酸化的抑制作用，而NO抑制剂L-硝基精氨酸甲酯(L-NAME)可显著阻断松弛素对体内胶原浓度的抑制作用。这些发现表明，松弛素信号通过RXFP1和依赖于nNOS-NO-cGMP的途径来抑制Smad2的磷酸化，并干扰转化生长因子-β1介导的肾脏肌成纤维细胞分化和胶原的产生。-Mookerjee，I.，Hewitson，T.D.，Halls，M.L.，Summers，R.J.，Mathai，M.L.，Bathgate，R.A.D.，Tregear，G.W.，Samuel，C.S.Relaxin通过RXFP1，一氧化氮途径和Smad2抑制肾脏肌成纤维细胞的分化。FASE B J.23,1219-1229(2009)
The hormone relaxin inhibits renal myofibroblast differentiation by interfering with TGF-beta 1/Smad2 signaling. However, the pathways involved in the relaxin-TGF-beta 1/Smad2 interaction remain unknown. This study investigated the signaling mechanisms by which human gene-2 (H2) relaxin regulates myofibroblast differentiation in vitro by examining its effects on mixed populations of fibroblasts and myofibroblasts propagated from injured rat kidneys. Cultures containing similar to 60-70% myofibroblasts were used to determine which relaxin receptors, G-proteins, and signaling pathways were involved in the H2 relaxin-mediated regulation of alpha-smooth muscle actin (alpha-SMA; a marker of myofibroblast differentiation). H2 relaxin only inhibited alpha-SMA immunostaining and collagen concentration in the presence of relaxin family peptide receptor 1 (RXFP1). H2 relaxin also induced a transient rise in cAMP in the presence of G(i/o) inhibition, and a sustained increase in extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. Furthermore, inhibition of neuronal nitric oxide synthase (nNOS), NO, and cGMP significantly blocked the inhibitory effects of relaxin on alpha-SMA and Smad2 phosphorylation, while the NO inhibitor, L-nitroarginine methyl ester (hydrochloride) (L-NAME) significantly blocked the inhibitory actions of relaxin on collagen concentration in vivo. These findings suggest that relaxin signals through RXFP1, and a nNOS-NO-cGMP-dependent pathway to inhibit Smad2 phosphorylation and interfere with TGF-beta 1-mediated renal myofibroblast differentiation and collagen production.- Mookerjee, I., Hewitson, T. D., Halls, M. L., Summers, R. J., Mathai, M. L., Bathgate, R. A. D., Tregear, G. W., Samuel, C. S. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J. 23, 1219-1229 (2009)