Department of Physiology, Box P7-3, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA.
Hypertension. 2013 Feb;61(2):465-71. doi: 10.1161/HYPERTENSIONAHA.111.202424. Epub 2012 Dec 3.
Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type 2 diabetes mellitus. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes mellitus. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro(10)]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared with control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro(11), D-Ala(12)]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared with control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3, and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro(11), D-Ala(12)]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro(11), D-Ala(12)]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mouse mast cell protease-4 or chymase/β-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/β-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared with control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute to the progression of diabetic kidney disease.
我们之前的工作表明，血管紧张素转换酶（ACE）非依赖性的肾脏内血管紧张素（ANG）II 的形成在 2 型糖尿病的微血管功能中起着重要作用。我们假设在糖尿病中存在从肾脏血管 ACE 依赖性向糜酶依赖性 ANGII 形成的转变。与对照组（db/m）相比，糖尿病（db/db）小鼠肾脏的肾髓质传入小动脉（AA）对 ACE 特异性、糜酶抗性的 ANG I 肽（[Pro(10)]ANGI）转化为 ANGII 的肾内转化的 AA 收缩反应显著降低。与对照组相比，糖尿病小鼠肾脏的肾内转化糜酶特异性、ACE 抗性的 ANG I 肽（[Pro(11)，D-Ala(12)]ANGI）为 ANGII 的 AA 反应显著增强。在糖尿病肾脏中，分别用 10、100 和 1000nmol/L [Pro(11)，D-Ala(12)]ANGI 刺激，AA 直径分别降低 9±2%、15±3%和 24±3%，对血管紧张素 1 型受体或糜酶特异性（JNJ-18054478）抑制的反应显著减弱。[Pro(11)，D-Ala(12)]ANGI 在对照组肾脏中未引起 AA 明显收缩。糜酶抑制可显著减弱糖尿病肾脏中 ANGII 诱导的 AA 收缩，但在对照组肾脏中无明显抑制作用。与对照组相比，糖尿病组织中鼠 mast 细胞蛋白酶-4 或糜酶/β-肌动蛋白 mRNA 表达显著增加 5.1±1.4 倍，而 ACE/β-肌动蛋白 mRNA 表达显著减少 0.42±0.08 倍。总之，在对照组中，ANGII 的肾内形成主要通过 ACE，而在糖尿病血管中则通过糜酶。总之，糜酶依赖性机制可能有助于糖尿病肾病的进展。
