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首页> 外文期刊>American Journal of Physiology >Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes.
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Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes.

机译：内皮素拮抗作用可阻止早期的EGFR反式激活，但不能增加糖尿病患者的基质金属蛋白酶活性。

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Although past studies have demonstrated decreased renal matrix metalloproteinase (MMP) activity in type 1 diabetes and in mesangial cells grown under high glucose conditions, renal MMP expression and activity in type 2 diabetes and the regulation of MMPs by profibrotic factors involved in diabetic renal complications such as endothelin-1 (ET-1) remained unknown. The renal expression and activity of MMPs in type 2 diabetic Goto-Kakizaki (GK) rats treated with vehicle or ET(A) receptor selective antagonist ABT-627 for 4 wk were assessed by gelatin zymography, fluorogenic gelatinase assay, and immunoblotting. In addition, expression and phosphorylation of epidermal growth factor receptor (EGFR) and connective tissue growth factor were evaluated by immunoblotting. Renal sections stained with Masson trichrome were used to investigate kidney structure. MMP-2 activity and protein levels were significantly increased in both cortical and medullary regions in the GK rats. Membrane-bound MMP (MT1-MMP), MMP-9, andfibronectin levels were also increased, and ABT-627 treatment did not have an effect on MMP activity and expression. Histological analysis of kidneys did not reveal any structural changes. Phosphorylation of EGFR was significantly increased in the diabetic animals, and ABT-627 treatment prevented this increase, suggesting ET-1-mediated transactivation of EGFR. These results suggest that there is early upregulation of renal MMPs in the absence of any kidney damage. Although the ET(A) receptor subtype is not involved in the early activation of MMPs in type 2 diabetes, ET-1 contributes to transactivation of growth-promoting and profibrotic EGFR.
机译：尽管过去的研究表明在高糖条件下生长的1型糖尿病和肾小球系膜细胞中肾基质金属蛋白酶（MMP）活性降低，但2型糖尿病中肾MMP的表达和活性以及糖尿病性肾脏并发症所涉及的纤维化因子对MMP的调节因为内皮素1（ET-1）仍然未知。通过明胶酶谱分析，荧光明胶酶测定和免疫印迹评估了用媒介物或ET（A）受体选择性拮抗剂ABT-627治疗2周的2型糖尿病Goto-Kakizaki（GK）大鼠的肾脏表达和MMP活性。另外，通过免疫印迹评估了表皮生长因子受体（EGFR）和结缔组织生长因子的表达和磷酸化。用Masson三色染色的肾脏切片用于研究肾脏结构。在GK大鼠的皮质和髓质区域MMP-2活性和蛋白质水平均显着增加。膜结合的MMP（MT1-MMP），MMP-9和纤连蛋白的水平也增加，并且ABT-627处理对MMP活性和表达没有影响。肾脏的组织学分析未发现任何结构变化。在糖尿病动物中，EGFR的磷酸化显着增加，而ABT-627处理阻止了这种增加，表明ET-1介导的EGFR反式激活。这些结果表明，在没有任何肾脏损害的情况下，肾脏MMP的早期上调。尽管ET（A）受体亚型不参与2型糖尿病MMP的早期活化，但ET-1有助于促进生长和纤维化的EGFR的反式激活。

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