胰激肽原酶对自发性高血压大鼠肾损害的保护作用

Nephroprotective Effects of Pancreatic Kininogenase in Spontaneously Hypertensive Rats

背景胰激肽原酶是一种糖蛋白,作用于激肽原,使之裂解生成激肽,激肽促进内皮细胞释放一氧化氮(NO)与前列腺素I2(PGl2),引起血管扩张、血管渗透性增加,从而发挥降压、保护肾脏、心脏等生理学作用。目的观察胰激肽原酶干预对自发性高血压大鼠(SHR)肾功能的影响,探讨激肽释放酶激肽系统在高血压及肾脏保护方面的可能机制。方法36周龄SPF级雄性SHR12只随机分成高血压对照组(B组)与高血压治疗组[C组,给予胰激肽原酶800U/(kg.d)灌胃治疗12周],每组各6只。另有年龄匹配的雄性WKY大鼠6只作为正常血压对照组(A组)。治疗前、后,观察3组大鼠血压、血肌酐(Scr)、尿素氮(BUN)、NO、6-酮-前列腺素F1a(6-K-PGF1a)及尿微量白蛋白(MAU)、尿β2微球蛋白(β2-MG)、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)浓度及肾脏组织病理改变,并用逆转录聚合酶链反应(RT-PCR)方法测定肾皮质组织型激肽释放酶mRNA的表达。结果胰激肽原酶治疗后C组血压较B组明显下降(P<0.01);MAU、β2-MG、NAG定量明显降低(P<0.01),血清NO、6-K-PGF1a水平升高(P<0.05);肾皮质组织型激肽释放酶mRNA表达水平增加(P<0.05)。对照组大鼠肾小球小动脉管壁增厚,管腔狭窄,个别小球硬化;胰激肽原酶治疗后肾小动脉结构正常,未见小球硬化。结论胰激肽原酶能显著减少尿微量蛋白、逆转肾小动脉硬化改变,保护肾功能,其机制可能与血压下降,血清NO、6-K-PGF1a水平及肾脏组织激肽释放酶水平升高有关。

Background Pancreatic kininogenase is a kind of glycoprotein, which converts kininogen into kinins. By promoting endothelial cells to release nitric oxide （NO） and prostaglandin I2 （ PGI2 ） leading to vasodilation and increase vascular permeability, kinins may lower blood pressure, protect renal and cardiac functions. Objective To study the effect of pancreatic kininogenase on renal function in spontaneously hypertensive rat （SHR） and explore the possible mechanism of kallikrein-kinin system in the development of hypertension and nephroprotection. Methods Twelve 36-week-old male SHRs were randomized into hypertension control group （group B, n= 6 ） or receive pancreatic kininogenase 800 U/（ kg · d）, ig group C for 12 weeks, n= 6. Six WKY rats were used as control （group A）. Blood pressure, urine microalbumin（MAU）, β2-microglobin（β2-MG） , N- acetyl-β-D-glucosaminidase（NAG）, NO and 6-Keto-PGF1a （6-K-PGF1a） were measured, and renal tissues were examined by light and electronic microscopy. The levels of tissue kallikrein mRNA were detected by RT-PCR. Results Compared with non-treated SHR, pancreatic kininogenase significantly decreased SBP （P〈0.01） and the excretion of MAU, β2-MG and NAG in urine （all P〈0.01 ）. Serum NO, plasma 6-K-PGF1a and tissue kallikrein mRNA expression in the kidneys were increased by pancreatic kininogenase treatment （P〈0. 05 ）. Pancreatic kininogenase ameliorate hypertrophy and sclerosis on the walls of arterioles, narrow in the lumina of these arterioles and hyalinization in some glomeruli seen in SHR. Conclusion Pancreatic kininogenase reduces the extentof proteinuria and attenuates functional and structural damages induced by hypertension, which was associated with increases in NO, PG12 and tissue kallikrein .