Antifibrotic Properties of Relaxin: In Vivo Mechanism of Action in Experimental Renal Tubulointerstitial Fibrosis
Antifibrotic Properties of Relaxin: In Vivo Mechanism of Action in Experimental Renal Tubulointerstitial Fibrosis
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DOI：
10.1210/en.2010-0286
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发表时间：
2010-10-01
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：
Hewitson, Tim D.;Ho, Wen Yang;Samuel, Chrishan S.
本研究探讨了抗纤维化激素松弛素在单侧输尿管梗阻（UUO）小鼠模型中的作用及其体内机制。重组人基因-2松弛素治疗的小鼠在UUO后维持3和9 d，评估肾脏纤维化。结果与未手术和未治疗的动物进行比较（d 0）。总胶原、胶原亚型（I、IV）、tgf - β 2生成、抗十肢瘫痪同源物2 （Smad2）磷酸化、肌成纤维细胞分化、有丝分裂和凋亡均在第3天和第9天逐渐增加（P < 0.05），而tgf - β 1生成增加，血管内皮生长因子表达（血管生成）减少（P < 0.05）。UUO后基质金属蛋白酶(MMP)-2的逐渐增加表明它与纤维生成增加有关。相反，MMP-9在第9天下降，而其抑制剂金属蛋白酶-1的组织抑制剂在UUO后逐渐下降。在UUO前4天对动物进行人基因-2松弛素预处理，在两个时间点改善了总胶原、胶原IV、Smad2磷酸化和肌成纤维细胞的增加（与未处理组相比均P < 0.05），抑制了tgf - β 2的产生和细胞增殖（与未处理组相比均P < 0.05），并在第9天有使血管内皮生长因子表达正常化的趋势，对tgf - β 1的产生或细胞凋亡没有影响。松弛素介导的MMPs和金属蛋白酶组织抑制剂在该模型中的调节与其抗纤维化特性不一致。当停止治疗时，松弛素的有益作用就消失了。这些发现表明，松弛素可以抑制早期和成熟阶段的小管间质纤维化，主要是通过抑制细胞增殖、肌成纤维细胞分化和胶原蛋白的产生。并非所有这些影响都与tgf - β - smad信号的变化相平行。（中国医学杂志，2010）
This study examined the efficacy and in vivo mechanism of action of the antifibrotic hormone, relaxin, in a mouse model of unilateral ureteric obstruction (UUO). Kidney fibrosis was assessed in recombinant human gene-2 relaxin-treated animals maintained for 3 and 9 d after UUO. Results were compared with untreated and unoperated animals (d 0). Total collagen, collagen subtypes (I, IV), TGF-beta 2 production, mothers against decapentaplegic homolog 2 (Smad2) phosphorylation, myofibroblast differentiation, mitosis, and apoptosis were all progressively increased by UUO (all P < 0.05 vs. d 0 group at d 3 and d 9), whereas TGF-beta 1 production was increased and vascular endothelial growth factor expression (angiogenesis) decreased at d 9 (both P < 0.05 vs. d 0). A progressive increase in matrix metalloproteinase (MMP)-2 after UUO suggested that it was reactive to the increased fibrogenesis. Conversely, MMP-9 was decreased at d 9, whereas its inhibitor tissue inhibitor of metalloproteinase-1 progressively decreased after UUO. Human gene-2 relaxin pretreatment of animals from 4 d prior to UUO ameliorated the increase in total collagen, collagen IV, Smad2 phosphorylation, and myofibroblasts at both time points (all P < 0.05 vs. untreated groups) and inhibited TGF-beta 2 production and cell proliferation (both P < 0.05 vs. untreated groups) with a trend toward normalizing vascular endothelial growth factor expression at d 9, with no effect on TGF-beta 1 production or apoptosis. The relaxin-mediated regulation of MMPs and tissue inhibitor of metalloproteinases in this model was not consistent with its antifibrotic properties. The beneficial effects of relaxin were lost when treatment was stopped. These findings establish that relaxin can inhibit both early and established phases of tubulointerstitial fibrosis, primarily by suppressing cell proliferation, myofibroblast differentiation, and collagen production. Not all of these effects paralleled changes to TGF-beta-Smad signaling. (Endocrinology 151: 4938-4948, 2010)