TGF-β concentration specifies differential signaling profiles of growth arrest/differentiation land apoptosis in podocytes
TGF-β concentration specifies differential signaling profiles of growth arrest/differentiation land apoptosis in podocytes
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DOI：
10.1681/asn.2004121055
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发表时间：
2005-11-01
影响因子：
13.6
通讯作者：
Böttinger, EP
中科院分区：
文献类型：
--
作者：
Wu, DT;Bitzer, M;Böttinger, EP
足细胞耗竭发生在大多数进展性肾小球疾病中，被认为是足细胞丢失而剩余的足细胞无法增殖所致。足细胞生长停止/分化和衰竭的潜在机制仍然知之甚少，但可能与转化生长因子-β有关，转化生长因子-β通常在受损的肾小球上调。转化生长因子-β是一种多功能细胞因子，调节大多数细胞的生长、分化和凋亡。关于转化生长因子-β信号在细胞周期控制和细胞凋亡中的功能特异性的决定因素仍然知之甚少。利用一个独特的条件永生化足细胞系统，研究表明，在非允许培养条件下，自分泌的转化生长因子-β2通过Smad3依赖的诱导细胞周期依赖的激酶抑制因子p15(Ink4b)(CDKN2B)诱导G0/G1期停滞和分化。当暴露于重组的转化生长因子-β1(或转化生长因子-β2)时，非允许培养的足细胞转换为G2/M期停滞和凋亡，选择性地在较高的转化生长因子-β浓度下，特别是与抑制CDKN2B和激活促凋亡的p38丝裂原活化蛋白激酶有关。因此，以浓度依赖的方式被转化生长因子-β激活的不同的信号特征被识别出来。足细胞中自分泌的转化生长因子-β2/Smad3/CDKN2B信号指定与足细胞分化相关的G0/G1期停滞，而增加转化生长因子-β浓度超过临界阈值则诱导与选择性p38丝裂原活化蛋白激酶激活和CDKN2B抑制相关的G2/M期阻滞和细胞凋亡。综上所述，这些结果提示了转化生长因子-β在体外对小鼠足细胞生长抑制和分化的新的功能需求，并证明了一个临界的转化生长因子-β浓度阈值可能指定了向促凋亡信号转导和细胞凋亡的分子开关。
Podocyte depletion occurs in most progressive glomerular diseases and is thought to result from podocyte loss while the remaining podocytes are unable to proliferate. The underlying mechanisms for podocyte growth arrest/differentiation and depletion remain poorly understood but may involve TGF-beta, which is typically upregulated in injured glomeruli. The TGF-beta are multifunctional cytokines that regulate growth, differentiation, and apoptosis in most cells. Determinants of functional specificity of TGF-beta signaling in cell-cycle control and apoptosis remain poorly understood. Using a unique system of conditionally immortalized podocytes, it is demonstrated that autocrine TGF-beta 2 induces G0/G1 arrest and differentiation under nonpermissive culture through Smad3-dependent induction of the cyclih-dependent kinase inhibitor p15(Ink4b) (Cdkn2b). When exposed to recombinant TGF-beta 1 (or TGF-beta 2), nonpermissive culture podocytes switch to G2/M arrest and apoptosis, selectively at advanced TGF-beta concentrations and specifically in association with suppression of Cdkn2b and activation of proapoptotic p38 mitogen-activated protein kinase. Thus, distinct signaling profiles activated in a concentration-dependent manner by TGF-beta were identified. Autocrine TGF-beta 2/Smad3/Cdkn2b signaling in podocytes specifies G0/G1 arrest associated with podocyte differentiation, whereas increasing TGF-beta concentrations beyond a critical threshold induces G2/M block and apoptosis associated with selective p38 mitogen-activated protein kinase activation and with suppression of Cdkn2b. In summary, the results suggest a new functional requirement of TGF-beta in growth arrest and differentiation of murine podocytes in vitro and demonstrate that a critical TGF-beta concentration threshold may specify a molecular switch to proapoptotic signaling profiles and apoptosis.