Kim Sung Min, Kim Nari, Lee Seoul, Kim Do Kyung, Lee Yu Min, Ahn Seon Ho, Song Ju Hung, Choi Bong Kyu, Wu Chuanyue, Jung Kyu Yong
Department of Pharmacology, Wonkwang University School of Medicine, Iksan 570-749, Korea.
Exp Mol Med. 2007 Aug 31;39(4):514-23. doi: 10.1038/emm.2007.57.
TGF-beta1-induced glomerular mesangial cell (GMC) injury is a prominent characteristic of renal pathology in several kidney diseases, and a ternary protein complex consisting of PINCH-1, integrin-linked kinase (ILK) and alpha-parvin plays a pivotal role in the regulation of cell behavior such as cell proliferation and hypertrophy. We report here that PINCH-1-ILK-alpha-parvin (PIP) complex regulates the TGF-beta1-induced cell proliferation and hypertrophy in cultured rat GMCs. When GMCs were treated with TGF-beta1 for 1, 2 and 3 days, the PIP complex formation was up-regulated after 1 day, but it was down-regulated on day 2. Cell numbers were significantly elevated on day 2, but dramatically decreased on day 3. In contrast, a significant increase in cellular protein contents was observed 3 days after TGF-beta1-treatment. TGF-beta1 induced early increase of caspase-3 activity. In GMCs incubated with TGF-beta1 for 2 days, cytosolic expression of p27(Kip1) was dramatically reduced, but its nuclear expression was remarkably elevated. A significantly decreased expression of phospho-Akt (Ser 473) was observed in the cells treated with TGF-beta1 for 1 day. TGF-beta1 induced early increase of phospho-p27(Kip1) (Thr 157) expression with subsequent decrease, and similar responses to TGF-beta1 were observed in the p38 phosphorylation (Thr 180/Thr 182). Taken together, TGF-beta1 differently regulates the PIP complex formation of GMCs in an incubation period-dependant fashion. The TGF-beta1-induced up- and down-regulation of the PIP complex formation likely contributes to the pleiotropic effects of TGF-beta1 on mesangial cell proliferation and hypertrophy through cellular localization of p27(Kip1) and alteration of Akt and p38 phosphorylation. TGF-beta1-induced alteration of the PIP complex formation may be importantly implicated in the development and progression of glomerular failure shown in several kidney diseases.
转化生长因子β1（TGF-β1）诱导的肾小球系膜细胞（GMC）损伤是多种肾脏疾病肾脏病理的一个突出特征，由PINCH-1、整合素连接激酶（ILK）和α-帕文组成的三元蛋白复合物在调节细胞增殖和肥大等细胞行为中起关键作用。我们在此报告，PINCH-1-ILK-α-帕文（PIP）复合物调节培养的大鼠GMC中TGF-β1诱导的细胞增殖和肥大。当GMC用TGF-β1处理1天、2天和3天时，PIP复合物形成在1天后上调，但在第2天下调。细胞数量在第2天显著升高，但在第3天急剧下降。相反，TGF-β1处理3天后观察到细胞蛋白含量显著增加。TGF-β1诱导caspase-3活性早期增加。在与TGF-β1孵育2天的GMC中，p27（Kip1）的胞质表达显著降低，但其核表达显著升高。在用TGF-β1处理1天的细胞中观察到磷酸化Akt（Ser 473）表达显著降低。TGF-β1诱导磷酸化p27（Kip1）（Thr 157）表达早期增加，随后降低，并且在p38磷酸化（Thr 180/Thr 182）中观察到对TGF-β1的类似反应。综上所述，TGF-β1以孵育时间依赖性方式不同地调节GMC的PIP复合物形成。TGF-β1诱导的PIP复合物形成的上调和下调可能通过p27（Kip1）的细胞定位以及Akt和p38磷酸化的改变，对TGF-β1对系膜细胞增殖和肥大的多效性作用有贡献。TGF-β1诱导的PIP复合物形成的改变可能在几种肾脏疾病中显示的肾小球衰竭的发生和发展中起重要作用。
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