Enhanced Renal Afferent Arteriolar Reactive Oxygen Species and Contractility to Endothelin-1 Are Associated with Canonical Wnt Signaling in Diabetic Mice.
Enhanced Renal Afferent Arteriolar Reactive Oxygen Species and Contractility to Endothelin-1 Are Associated with Canonical Wnt Signaling in Diabetic Mice.
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糖尿病小鼠肾传入小动脉活性氧和内皮素-1 收缩性的增强与典型 Wnt 信号转导相关
DOI：
10.1159/000490334
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发表时间：
2018
影响因子：
2.8
通讯作者：
Lai EY
中科院分区：
文献类型：
--
作者：
Zhang S;Huang Q;Wang Q;Wang Q;Cao X;Zhao L;Xu N;Zhuge Z;Mao J;Fu X;Liu R;Wilcox CS;Patzak A;Li L;Lai EY
背景/目标：经典Wnt信号通路参与氧化应激、血管病变和糖尿病，但其在糖尿病肾微血管功能障碍中的作用尚不清楚。我们测试了糖尿病小鼠肾传入小动脉中增强的经典Wnt信号传导增加活性氧（ROS）和内皮素-1（ET-1）收缩的假设。方法：采用链脲佐菌素（STZ）诱导的C5 7 B1/6小鼠糖尿病模型和对照组，分别给予舒林酸（40 mg·kg-1·d-1）和Wnt信号通路阻断剂（40 mg·kg<sup>-1</sup>·d<sup>-1</sup>）。通过测量传入小动脉直径的变化来测量ET-1收缩。分别用荧光探针法、免疫印迹法和比色法检测<sub>H2</sub><sub>O2</sub>、<sub>O2</sub><sup>-</sup>结果：与对照组相比，糖尿病小鼠传入小动脉O2<sup>-</sup>（+ 84%）和<sub>H2</sub><sub>O2</sub>（+ 91%）增加，对10<sup>- 8</sup> mol·l<sup>-1</sup>ET-1的反应性增强（-72% vs. -43%，P<0.0 5），过氧化氢酶（CAT）和超氧化物歧化酶2（SOD 2）的蛋白表达和活性降低。<sub></sub>ET-1可进一步增加糖尿病小鼠小动脉<sub>O2</sub><sup>-，</sup>PEG-SOD可减少ET-1引起的收缩，而ET-1对<sub>H2</sub>O2<sub>无</sub>在糖尿病小鼠的肾小球前血管中，Wnt信号蛋白β-catenin上调（β-catenin/β-catenin降低3.3倍），而糖原合成酶激酶-3 β（GSK-3β）下调（p-GSK-3β/ GSK-3β增加2.6倍）。舒林酸使Wnt信号蛋白、小动脉O2<sup>-</sup>、<sub>H2</sub><sub>O2</sub>和ET-1收缩正常化，同时使糖尿病小鼠微血管过氧化氢酶和SOD 2表达加倍。<sub></sub>结论：糖尿病时ROS，尤其<sub>是H2</sub>O2<sub>的增加</sub>，参与了ET-1对糖尿病小动脉的反应，这种反应与Wnt信号密切相关。针对Wnt信号通路的抗氧化药理学策略可能改善糖尿病肾病的血管功能。
Background/Aims: Canonical Wnt signaling is involved in oxidative stress, vasculopathy and diabetes mellitus but its role in diabetic renal microvascular dysfunction is unclear. We tested the hypothesis that enhanced canonical Wnt signaling in renal afferent arterioles from diabetic mice increases reactive oxygen species (ROS) and contractions to endothelin-1 (ET-1). Methods: Streptozotocin-induced diabetes or control C57Bl/6 mice received vehicle or sulindac (40 mg·kg<sup>-1</sup>·day<sup>-1</sup>) to block Wnt signaling for 4 weeks. ET-1 contractions were measured by changes of afferent arteriolar diameter. Arteriolar H<sub>2</sub>O<sub>2</sub>, O<sub>2</sub> <sup>-</sup>, protein expression and enzymatic activity were assessed using sensitive fluorescence probes, immunoblotting and colorimetric assay separately. Results: Compared to control, diabetic mouse afferent arteriole had increased O<sub>2</sub><sup>-</sup> (+ 84%) and H<sub>2</sub>O<sub>2</sub> (+ 91%) and enhanced responses to ET-1 at 10<sup>-8</sup> mol·l<sup>-1</sup> (-72±4% of versus -43±4%, P< 0.05) accompanied by reduced protein expressions and activities for catalase and superoxide dismutase 2 (SOD2). Arteriolar O<sub>2</sub> <sup>-</sup> was increased further by ET-1 and contractions to ET-1 reduced by PEG-SOD in both groups whereas H<sub>2</sub>O<sub>2</sub> unchanged by ET-1 and contractions were reduced by PEG-catalase selectively in diabetic mice. The Wnt signaling protein β-catenin was upregulated (3.3-fold decrease in p-β-catenin/β-catenin) while the glycogen synthase kinase-3β (GSK-3β) was downregulated (2.6-fold increase in p-GSK-3β/ GSK-3β) in preglomerular vessels of diabetic mice. Sulindac normalized the Wnt signaling proteins, arteriolar O<sub>2</sub> <sup>-</sup>, H<sub>2</sub>O<sub>2</sub> and ET-1 contractions while doubling microvascular catalase and SOD2 expression in diabetic mice. Conclusion: Increased ROS, notably H<sub>2</sub>O<sub>2</sub> contributes to enhanced afferent arteriolar responses to ET-1 in diabetes, which is closely associated with Wnt signaling. Antioxidant pharmacological strategies targeting Wnt signaling may improve vascular function in diabetic nephropathy.
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影响因子：
16.6
作者：
Lee, Ho-Jin;Wang, Nick X.;Shi, De-Li;Zheng, Jie J.
通讯作者：
Zheng, Jie J.
超氧化物调节小鼠传入动脉的肌源性收缩。
DOI：
10.1161/hypertensionaha.111.170472
发表时间：
2011-10
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Lai EY;Wellstein A;Welch WJ;Wilcox CS
通讯作者：
Wilcox CS
DOI：
10.1111/apha.12745
发表时间：
2016-10
期刊：
Acta physiologica (Oxford, England)
影响因子：
--
作者：
Huang Q;Wang Q;Zhang S;Jiang S;Zhao L;Yu L;Hultström M;Patzak A;Li L;Wilcox CS;Lai EY
通讯作者：
Lai EY
影响因子：
2.3
作者：
Granstam, Sven-Olof;Granstam, Elisabet
通讯作者：
Granstam, Elisabet
影响因子：
7.7
作者：
Ceriello, A;delloRusso, P;Cerutti, P
通讯作者：
Cerutti, P