Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor
Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor
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DOI：
10.1152/ajprenal.00437.2011
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Girolami, Jean-Pierre
中科院分区：
文献类型：
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作者：
Blaes, Nelly;Pecher, Christiane;Girolami, Jean-Pierre
Blaes N、Pecher C、Mehrenberger M、Cellier E、Praddaude F、Chevalier J、Tack I、Couture R、Girolami JP。缓激肽通过 B2 激肽受体抑制系膜细胞中高葡萄糖和生长因子诱导的胶原蛋白合成。 Am J Physiol Renal Physiol 303：F293-F303，2012 年。首次发表于 2012 年 5 月 9 日； doi:10.1152/ajprenal.00437.2011.-系膜基质扩张是导致肾小球硬化症和慢性肾脏疾病的早期病变。血管紧张素 I 转换酶抑制剂 (ACEI) 可以达到有益效果，同时也有利于缓激肽 (BK) B2 受体 (B2R) 的激活。为了明确其潜在机制，我们假设 B2R 激活可能是系膜细胞 (MC) 中胶原蛋白合成的负调节因子。我们研究了 BK 对 MC 中胶原蛋白合成和信号传导的影响。通过细胞间粘附分子-1 (ICAM-1) 表达来评估炎症。 BK 抑制高葡萄糖、上皮生长因子 (EGF) 和转化生长因子-β (TGF-β) 刺激的 I 型和 IV 型胶原合成，但不改变 ICAM-1。胶原蛋白合成的抑制是 B2R 介导的，但不是 B1R 介导的。 PKC 或磷脂酰肌醇 3-激酶 (PI3K) 抑制剂模仿 BK 效应。 B2R 激活抑制 TGF-β 和 EGF 诱导的 Erk1/2、Smad2/3、Akt S473 和 EGFR 磷酸化。磷酸酶抑制剂可防止 BK 效应。在链脲佐菌素糖尿病啮齿动物中评估了 B2R 对系膜基质扩张的体内影响。 B2R 缺失会增加糖尿病小鼠的系膜基质扩张和白蛋白尿。在糖尿病大鼠中，ACEI 可预防基质扩张和蛋白尿，但 ACEI 和 B2R 拮抗剂联合治疗则不能预防。一致地，ACEI 可以恢复糖尿病肾小球降低的 BK 含量。总之，B2R 激活不足会加剧糖尿病啮齿动物的系膜基质扩张，而 B2R 激活则通过针对 Erk1/2 和 Akt（EGF 和 TGF-β 激活的常见途径）的机制减少 MC 胶原合成。总而言之，这些数据支持 B2R 激活具有抗纤维化作用的假设。
Blaes N, Pecher C, Mehrenberger M, Cellier E, Praddaude F, Chevalier J, Tack I, Couture R, Girolami JP. Bradykinin inhibits high glucose-and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor. Am J Physiol Renal Physiol 303: F293-F303, 2012. First published May 9, 2012; doi:10.1152/ajprenal.00437.2011.-Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-beta (TGF-beta) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-beta- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-beta. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.