Leptin stimulates type I collagen production in db/db mesangial cells:: Glucose uptake and TGF-β type II receptor expression
Leptin stimulates type I collagen production in db/db mesangial cells:: Glucose uptake and TGF-β type II receptor expression
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DOI：
10.1046/j.1523-1755.2001.0590041315.x
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发表时间：
2001-04-01
影响因子：
19.6
通讯作者：
Ziyadeh, FN
中科院分区：
文献类型：
--
作者：
Han, DC;Isono, M;Ziyadeh, FN
背景。血清瘦素水平与脂肪细胞质量相关，在大量肥胖和2型糖尿病患者中，瘦素水平升高，这是肾小球硬化发展的重要危险因素。我们之前在培养的肾小球内皮细胞中表明，瘦素刺激细胞增殖和促前体细胞因子转化生长因子- β 1 （tgf - β 1）的表达。虽然瘦素对下丘脑调节能量稳态的作用是众所周知的，但对肾脏，特别是对肾小球系膜细胞的作用尚不清楚。肥胖、糖尿病db/db小鼠缺乏功能性全长Ob-Rb瘦素受体，是评估高瘦素血症对表达其他受体亚型的外周组织影响的合适模型。在培养的db/db小鼠系膜细胞中评估瘦素对葡萄糖摄取、tgf - β系统和I型胶原生成的影响。采用磷脂酰肌醇-3激酶（PI-3K）抑制剂研究PI-3K对瘦素的调节作用。通过逆转录聚合酶链反应，在非糖尿病db/m和糖尿病db/db小鼠的肾脏和系膜细胞中均存在短形式的瘦素受体（Ob-Ra），但不存在Ob-Rb。在db/db系膜细胞中，瘦素增加2-脱氧-d -葡萄糖（2DOG）摄取剂量依赖性，并刺激TGF-P II型受体（T β RII）和α 1(I)胶原蛋白的基因表达，但不刺激tgf - β 1。瘦素也增加了I型胶原蛋白的蛋白生成（酶联免疫吸附测定）。瘦素刺激的2DOG摄取和I型胶原生成均被PI-SK抑制剂LY294002抑制。经瘦素预处理的系膜细胞对外源性TGF-beta1的反应性增强，暴露于低剂量TGF-beta1 （0.5 ng/mL）的瘦素预处理细胞中I型胶原蛋白的产量更高。添加tgf - β 1 （2 ng/mL）和瘦素（100 ng/mL）比单独添加tgf - β 1或瘦素更能增加I型胶原的生成。瘦素通过pi - 3k依赖途径增加db/db系膜细胞的葡萄糖摄取和I型胶原蛋白。我们推测，瘦素水平升高可能通过短型瘦素受体传递信号，上调T β RII，激活肾小球内tgf - β系统，这可能导致肥胖或2型糖尿病的肾小球硬化。
Background. Serum leptin levels correlate with fat cell mass and are elevated in patients with massive obesity and type 2 diabetes mellitus, which are strong risk factors for the development of glomerulosclerosis. We have previously shown in cultured glomerular endothelial cells that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine transforming growth factor-beta1 (TGF-beta1). Although the effect of leptin on the hypothalamus to regulate energy homeostasis is well known, the effect of leptin on the kidney, and specifically on the glomerular mesangial cell, is unclear.Methods. The obese, diabetic db/db mouse, which lacks the functional full-length Ob-Rb leptin receptor, is a suitable model to assess the effects of hyperleptinemia on peripheral tissues that express other receptor isoforms. The effects of leptin on glucose uptake, the TGF-beta system, and type I collagen production were evaluated in db/db mouse mesangial cells in culture. A phosphatidylinositol-3 kinase (PI-3K) inhibitor was used to assess the role of PI-3K in mediating the effects of leptin.Results. A short form of the leptin receptor (Ob-Ra), but not Ob-Rb, was present by reverse transcription-polymerase chain reaction in the kidney and mesangial cells of both nondiabetic db/m and diabetic db/db mice. In db/db mesangial cells, leptin increased 2-deoxy-D-glucose (2DOG) uptake dose dependently and stimulated gene expression of TGF-P type II receptor (T beta RII) and alpha1(I) collagen, but not TGF-beta1. Protein production of type I collagen (enzyme-linked immunosorbent assay) was also increased by leptin. Both leptin-stimulated 2DOG uptake and type I collagen production were suppressed by a PI-SK inhibitor, LY294002. Mesangial cells pretreated with leptin exhibited increased responsiveness to exogenous TGF-beta1, as evidenced by a greater production of type I collagen protein in leptin-pretreated cells exposed to low-dose TGF-beta1 (0.5 ng/mL). The addition of both TGF-beta1 (2 ng/mL) and leptin (100 ng/mL) increased type I collagen production more than addition of either TGF-beta1 or leptin alone.Conclusions. Leptin increases glucose uptake and type I collagen in db/db mesangial cells through a PI-3K-dependent pathway. We postulate that increased leptin levels may transmit a signal through the short-form leptin receptor to up-regulate T beta RII and activate the intraglomerular TGF-beta system, which may contribute to the glomerulosclerosis of obesity or type 2 diabetes.