INSERM U 1138, Cordeliers Research Center, Paris, France.
Paris Descartes University, Paris, France.
Sci Rep. 2017 Aug 25;7(1):9410. doi: 10.1038/s41598-017-09721-0.
Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemia-reperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R-agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42-52% and IS by 66-71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes.
激肽释放酶-激肽系统的激活增强了心脏和肾脏对缺血的耐受能力。在这里，我们研究了激肽 B1 或 B2 受体（R）选择性激动剂在糖尿病和非糖尿病小鼠脑缺血再灌注中的作用。组织激肽原缺乏小鼠（TK）评估了内源性激肽的作用。小鼠在 1 型糖尿病诱导 8 周后接受 60 分钟大脑中动脉闭塞（MCAO）。在再灌注时开始使用 B1R、B2R 激动剂或生理盐水进行治疗。在损伤后 0、1 和 2 天测量神经功能缺损（ND）、梗死面积（IS）和脑水含量（BWC）。MCAO 在糖尿病小鼠中引起了明显的 ND、死亡率和 IS。B2R 激动剂使非糖尿病和糖尿病小鼠的 ND 和死亡率分别增加到 60%和 80%，其机制涉及血流动力学衰竭和肾功能不全。与野生型同窝仔相比，TK 小鼠的 ND 和 IS 减少，这与 B2R 活性的抑制有关。缺血性脑内 B1R mRNA 水平增加，但 B1R 激动剂对非糖尿病小鼠的 ND、死亡率或 IS 没有影响。相比之下，在糖尿病小鼠中，两种剂量的 B1R 激动剂显著降低了 42-52%的 ND 和 66-71%的 IS，对 BWC 或肾功能没有影响。这表明 B1R 激动剂对糖尿病患者的脑保护具有潜在的治疗意义。
