Inhibition of Autoregulated TGFβ Signaling Simultaneously Enhances Proliferation and Differentiation of Kidney Epithelium and Promotes Repair Following Renal Ischemia
Inhibition of Autoregulated TGFβ Signaling Simultaneously Enhances Proliferation and Differentiation of Kidney Epithelium and Promotes Repair Following Renal Ischemia
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DOI：
10.2353/ajpath.2009.080295
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发表时间：
2009-04-01
影响因子：
6
通讯作者：
Venkatachalam, Manjeri A.
中科院分区：
文献类型：
--
作者：
Geng, Hui;Lan, Rongpei;Venkatachalam, Manjeri A.
我们研究了自分泌转化生长因子(TGF) β在肾上皮中的信号传导。培养的近端小管细胞显示出受调控的信号，在对数期生长期间高，在接触抑制分化期间低，并在损伤上皮再生期间迅速增加。信号的自调节与TGF β受体和Smad7水平相关，但与活性TGF β无关，活性TGF β在生长培养基中几乎无法测量。低受体和高Smad7水平的融合分化细胞对饱和浓度的外源提供的活性TGF - β反应迟钝，表明TGF - β信号稳态是通过细胞密度依赖性调节信号中间体实现的。TGF β I型受体Alk5激酶的拮抗作用显著加速了稀疏增殖培养中分化的诱导，并在损伤融合培养的再生细胞中更好地保留了分化特征。Alk5拮抗加速了近端小管原代培养细胞的分化，同时增加了细胞的增殖。因此，alk5抑制的原代培养比未处理的培养更快地形成融合、分化的单层。此外，用Alk5拮抗剂治疗可以促进肾修复，这反映在体内缺血损伤后恢复阶段小管分化增加和小管间质病理减少。我们的研究结果表明，增殖的近端小管细胞中的自分泌TGF β信号超过了生理再生所需的水平。为此，TGF β信号在上皮再生的小管修复过程中是冗余的和不适应的。（美国病理学杂志，2009,174:1291-1308;DOI: 10.2353/ajpath.2009.080295）
We studied autocrine transforming growth factor (TGF)beta signaling in kidney epithelium. Cultured proximal tubule cells showed regulated signaling that was high during log-phase growth, low during contact-inhibited differentiation, and rapidly increased during regeneration of wounded epithelium. Autoregulation of signaling correlated with TGF beta receptor and Smad7 levels, but not with active TGF beta, which was barely measurable in the growth medium. Confluent differentiated cells with low receptor and high Smad7 levels exhibited blunted responses to saturating concentrations of exogenously provided active TGF beta, suggesting that TGF beta signaling homeostasis was achieved by cell density-dependent modulation of signaling intermediates. Antagonism of Alk5 kinase, the TGF beta type I receptor, dramatically accelerated the induction of differentiation in sparse, proliferating cultures and permitted better retention of differentiated features in regenerating cells of wounded, confluent cultures. Alk5 antagonism accelerated the differentiation of cells in proximal tubule primary cultures while simultaneously increasing their proliferation. Consequently, Alk5-inhibited primary cultures formed confluent, differentiated monolayers faster than untreated cultures. Furthermore, treatment with an Alk5 antagonist promoted kidney repair reflected by increased tubule differentiation and decreased tubulo-interstitial pathology during the recovery phase following ischemic injury in vivo. Our results show that autocrine TGF beta signaling in proliferating proximal tubule cells exceeds the levels that are necessary for physiological regeneration. To that end, TGF beta signaling is redundant and maladaptive during tubule repair by epithelial regeneration. (Am J Pathol 2009, 174:1291-1308; DOI: 10.2353/ajpath.2009.080295)