血管紧张素II通过转化生长因子-β和血管内皮生长因子信号通路刺激小鼠足细胞中α3(IV)胶原蛋白的产生：对糖尿病肾小球病的影响。
Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy.
作者信息
Chen Sheldon, Lee Joseph S, Iglesias-de la Cruz M C, Wang Amy, Izquierdo-Lahuerta Adriana, Gandhi Nisha K, Danesh Farhad R, Wolf Gunter, Ziyadeh Fuad N
机构信息
Renal-Electrolyte and Hypertension Division of the University of Pennsylvania, Philadelphia, PA, USA.
出版信息
Nephrol Dial Transplant. 2005 Jul;20(7):1320-8. doi: 10.1093/ndt/gfh837. Epub 2005 Apr 19.
BACKGROUND
The podocyte is bathed in an angiotensin II (AngII)-rich ultrafiltrate, but the impact of AngII on podocyte pathobiology is not well known. Because podocytes play a direct role in the glomerular basement membrane (GBM) thickening of diabetes, the alpha3(IV) collagen chain was examined. Podocyte expression of alpha3(IV) collagen may involve the transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems.
METHODS
Cultured mouse podocytes were treated with various doses of AngII for selected periods of time, with or without inhibitors of TGF-beta and VEGF signalling, SB-431542 and SU5416, respectively. TGF-beta1 and VEGF were assayed by enzyme-linked immunosorbent assay (ELISA); alpha3(IV) collagen, TGF-beta type II receptor and phospho-Smad2 were assayed by immunoblotting.
RESULTS
AngII >or=10(-10) M was found to stimulate the production of alpha3(IV) collagen significantly in as short a time as 3 h. The expression of alpha3(IV) collagen was influenced by the TGF-beta system, but AngII did not increase the podocyte's production of TGF-beta1 ligand; rather, it increased the expression of the TGF-beta type II receptor and activated the TGF-beta signalling system through Smad2. Despite the TGF-beta receptor upregulation, synergy between AngII and TGF-beta1 to boost alpha3(IV) collagen production was not observed. However, blockade of TGF-beta signalling with SB-431542 prevented AngII from stimulating alpha3(IV) collagen production. Podocyte expression of alpha3(IV) collagen was also increased by the autocrine activity of VEGF. Podocytes were stimulated to secrete VEGF by 10(-10) M or higher AngII after 48 h. Blockade of the endogenous VEGF activity by SU5416 prevented AngII-stimulated alpha3(IV) collagen production.
CONCLUSIONS
AngII stimulates the podocyte to produce alpha3(IV) collagen protein via mechanisms involving TGF-beta and VEGF signalling. Alterations in alpha3(IV) collagen production may contribute to GBM thickening and perhaps proteinuria in diabetes.
背景
足细胞浸浴在富含血管紧张素II（AngII）的超滤液中，但AngII对足细胞病理生物学的影响尚不清楚。由于足细胞在糖尿病肾小球基底膜（GBM）增厚中起直接作用，因此对α3（IV）胶原链进行了检测。足细胞中α3（IV）胶原的表达可能涉及转化生长因子-β（TGF-β）和血管内皮生长因子（VEGF）系统。
方法
用不同剂量的AngII处理培养的小鼠足细胞特定时间，分别添加或不添加TGF-β和VEGF信号抑制剂SB-431542和SU5416。通过酶联免疫吸附测定（ELISA）检测TGF-β1和VEGF；通过免疫印迹检测α3（IV）胶原、TGF-β II型受体和磷酸化Smad2。
结果
发现AngII≥10⁻¹⁰ M在短短3小时内就能显著刺激α3（IV）胶原的产生。α3（IV）胶原的表达受TGF-β系统影响，但AngII并未增加足细胞TGF-β1配体的产生；相反，它增加了TGF-β II型受体的表达，并通过Smad2激活了TGF-β信号系统。尽管TGF-β受体上调，但未观察到AngII与TGF-β1之间协同促进α3（IV）胶原产生的作用。然而，用SB-431542阻断TGF-β信号可阻止AngII刺激α3（IV）胶原的产生。VEGF的自分泌活性也增加了足细胞中α3（IV）胶原的表达。48小时后，10⁻¹⁰ M或更高浓度的AngII刺激足细胞分泌VEGF。用SU5416阻断内源性VEGF活性可阻止AngII刺激的α3（IV）胶原产生。
结论
AngII通过涉及TGF-β和VEGF信号的机制刺激足细胞产生α3（IV）胶原蛋白。α3（IV）胶原产生的改变可能导致糖尿病中GBM增厚以及可能的蛋白尿。
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