{'fraction_non_alphanumeric': 0.05021616228799468, 'fraction_numerical': 0.02560691719321583, 'mean_word_length': 4.921259842519685, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Kininase I Inhibition Prevents Angiotensin II‐Induced Hypertension and Target Organ Damage

Activation of the kinin B1 receptor (B1R), a major component of the kallikrein kinin system (KKS), is associated with the pathogenesis of hypertension. Kininase I (or carboxypeptidase N/M; CPN/CPM), an enzyme primarily responsible for the synthesis of endogenous B1R agonist, has been implicated in the progression of cardiovascular diseases. However, the exact role of kininase I in hypertension has not been investigated. Our preliminary data shows that CPN activity is significantly increased in the brain of angiotensin (Ang) II‐induced hypertensive mice compared to vehicle treated mice (Ang II: 7.1 +0.4 AU/min vs. vehicle: 2.8 +0.3 AU/min, n=5, p<0.05). In this study, our objective was to clarify the role of kininase I in the pathogenesis of hypertension, particularly the effects of this enzyme on blood pressure, cardiac and renal hypertrophy. We hypothesized that inhibition of kininase I will attenuate the development of Ang II‐induced hypertension and target organ damage. To test this hypothesis, 12‐week old male and female C57BL/6NJ wild‐type (WT) and CPN gene deleted (CPNKO) mice, were administered Ang II (600 ng/kg/min; 2 weeks) or saline (vehicle) via osmotic minipumps. Blood pressure was measured using radio telemetry probes and hypertrophy was assessed in the heart and kidney after 14 days of Ang II‐infusion, using weight/tibial length. Baseline blood pressure was similar between WT and CPNKO mice (102 +2 mmHg vs. 104 +2 mmHg). Ang II‐infusion significantly increased the blood pressure in WT mice compared to saline infused mice (147 +5 mmHg, n=5, p<0.05). This Ang II‐increased blood pressure response was attenuated in CPNKO mice (125 +4 mmHg, n=5, p<0.01). Both male and female CPNKO mice did not show any significant differences in blood pressure following Ang II‐infusion. In addition, Ang II‐infusion also induced significant cardiac (heart weight/tibia length: 8.5 +0.9 vs. 6.8 +0.6 mg/mm) and renal (kidney weight/tibia length: 11.8 +1.5 vs. 8.7 +0.9 mg/mm) hypertrophy in WT mice compared to vehicle treated mice. However, CPNKO mice exhibited an attenuation in cardiac and renal hypertrophy following Ang II administration. Furthermore, Ang II‐infusion increased collagen deposition in the heart, measured by picrosirius red staining, which was attenuated in CPNKO mice (percent area 9.8 +1.4 vs. 7.2 +1.4). Ang II‐infusion also significantly increased B1R gene and protein expression in the hypothalamus, heart, kidney, and aorta of WT mice, but this expression was abrogated in CPNKO mice. In conclusion, our data suggest that CPN gene deletion protects from Ang II‐induced hypertension and target organ damage, and indirectly prevents the B1R activation. This is the first evidence to show that inhibition of kininase I prevents the development of Ang II‐induced hypertension. Targeting kininase I might be a novel therapeutic approach for the treatment of hypertension.