Velkoska Elena, Patel Sheila K, Griggs Karen, Pickering Raelene J, Tikellis Chris, Burrell Louise M
Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
PLoS One. 2015 Mar 18;10(3):e0118758. doi: 10.1371/journal.pone.0118758. eCollection 2015.
Angiotensin converting enzyme (ACE) 2 is an important modulator of the renin angiotensin system (RAS) through its role to degrade angiotensin (Ang) II. Depletion of kidney ACE2 occurs following kidney injury due to renal mass reduction and may contribute to progressive kidney disease. This study assessed the effect of diminazine aceturate (DIZE), which has been described as an ACE2 activator, on kidney ACE2 mRNA and activity in rats with kidney injury due to subtotal nephrectomy (STNx). Sprague Dawley rats were divided into Control groups or underwent STNx; rats then received vehicle or the DIZE (s.c. 15 mg/kg/day) for 2 weeks. STNx led to hypertension (P<0.01), kidney hypertrophy (P<0.001) and impaired kidney function (P<0.001) compared to Control rats. STNx was associated with increased kidney cortical ACE activity, and reduced ACE2 mRNA in the cortex (P<0.01), with reduced cortical and medullary ACE2 activity (P<0.05), and increased urinary ACE2 excretion (P<0.05) compared to Control rats. Urinary ACE2 activity correlated positively with urinary protein excretion (P<0.001), and negatively with creatinine clearance (P=0.04). In STNx rats, DIZE had no effect on blood pressure or kidney function, but was associated with reduced cortical ACE activity (P<0.01), increased cortical ACE2 mRNA (P<0.05) and increased cortical and medullary ACE2 activity (P<0.05). The precise in vivo mechanism of action of DIZE is not clear, and its effects to increase ACE2 activity may be secondary to an increase in ACE2 mRNA abundance. In ex vivo studies, DIZE did not increase ACE2 activity in either Control or STNx kidney cortical membranes. It is not yet known if chronic administration of DIZE has long-term benefits to slow the progression of kidney disease.
血管紧张素转换酶（ACE）2是肾素血管紧张素系统（RAS）的重要调节因子，其作用是降解血管紧张素（Ang）II。肾实质减少导致肾损伤后，肾脏ACE2会减少，这可能会导致进行性肾病。本研究评估了已被描述为ACE2激活剂的乙酰半胱氨酸嗪（DIZE）对因肾大部切除术（STNx）导致肾损伤的大鼠肾脏ACE2 mRNA和活性的影响。将Sprague Dawley大鼠分为对照组或进行STNx手术；然后大鼠接受载体或DIZE（皮下注射，15 mg/kg/天），持续2周。与对照大鼠相比，STNx导致高血压（P<0.01）、肾脏肥大（P<0.001）和肾功能受损（P<0.001）。与对照大鼠相比，STNx与肾脏皮质ACE活性增加、皮质中ACE2 mRNA减少（P<0.01）、皮质和髓质ACE2活性降低（P<0.05）以及尿ACE2排泄增加（P<0.05）有关。尿ACE2活性与尿蛋白排泄呈正相关（P<0.001），与肌酐清除率呈负相关（P=0.04）。在STNx大鼠中，DIZE对血压或肾功能没有影响，但与皮质ACE活性降低（P<0.01）、皮质ACE2 mRNA增加（P<0.05）以及皮质和髓质ACE2活性增加（P<0.05）有关。DIZE在体内的确切作用机制尚不清楚，其增加ACE2活性的作用可能是ACE2 mRNA丰度增加的继发效应。在体外研究中，DIZE在对照或STNx肾脏皮质膜中均未增加ACE2活性。目前尚不清楚长期给予DIZE是否对减缓肾病进展具有长期益处。
