Schießl Ina Maria, Kattler Veronika, Castrop Hayo
Institute of Physiology, University of Regensburg, Regensburg, Germany.
Institute of Physiology, University of Regensburg, Regensburg, Germany
J Pharmacol Exp Ther. 2015 May;353(2):299-306. doi: 10.1124/jpet.114.222125. Epub 2015 Feb 13.
Angiotensin-converting enzyme (ACE) inhibitors are commonly used antiproteinuric drugs. Here we assessed the effect of the ACE inhibitor enalapril on the glomerular sieving coefficient of albumin (GSCA) using intravital multiphoton microscopy. Munich Wistar Frömter (MWF) rats were used as a model of hypertension-related glomerular lesions. Young (9-week-old) MWF rats were nonproteinuric, similar to what was observed in control Wistar rats. However, urinary albumin excretion in the MWF rats gradually increased during aging, averaging 0.00062 ± 0.0001 at age 9 weeks and 0.0054 ± 0.0003 (mg/mOsmol per liter) at age 52 weeks (P < 0.0001). Albuminuria in aged MWF rats was accompanied by structural changes, which were indicative of glomerular lesions. The GSCA was low in young MWF rats but increased markedly during aging, averaging 0.00057 ± 4.7 × 10(-5) (n = 25) in young MWF rats and 0.0027 ± 0.00036 in 52-week-old MWF rats (n = 36; P < 0.0001). Treatment of proteinuric 12-month-old MWF rats with enalapril over a 4-week period reduced the GSCA from 0.0027 ± 0.00036 to 0.00139 ± 0.00013 (P = 0.0005). Similarly, urinary albumin excretion was reduced, averaging 0.0051 ± 0.0003 and 0.0036 ± 0.0005 mg/mOsmol per liter before and after enalapril administration, respectively (P = 0.0089). In parallel, enalapril treatment reduced the mean arterial blood pressure (144.6 ± 6.5 mm Hg in untreated versus 110.9 ± 0.6 mm Hg in enalapril-treated MWF rats) and increased the glomerular filtration rate from 1.64 ± 0.3 ml/min to 3.58 ± 0.3 ml/min (P = 0.0025 versus baseline). In summary, enalapril reduced the GSCA in proteinuric MWF rats, which was paralleled by a similar reduction in urinary albumin excretion. These data suggest that glomerular rather than tubular mechanisms account for the beneficial antiproteinuric effects of the ACE inhibitor.
血管紧张素转换酶（ACE）抑制剂是常用的抗蛋白尿药物。在此，我们使用活体多光子显微镜评估了ACE抑制剂依那普利对白蛋白肾小球滤过系数（GSCA）的影响。慕尼黑Wistar Frömter（MWF）大鼠被用作高血压相关肾小球病变的模型。年轻（9周龄）的MWF大鼠无蛋白尿，与对照Wistar大鼠的情况相似。然而，MWF大鼠的尿白蛋白排泄在衰老过程中逐渐增加，9周龄时平均为0.00062±0.0001，52周龄时为0.0054±0.0003（毫克/毫渗摩尔每升）（P<0.0001）。老年MWF大鼠的蛋白尿伴有结构变化，这表明存在肾小球病变。年轻MWF大鼠的GSCA较低，但在衰老过程中显著增加，年轻MWF大鼠平均为0.00057±4.7×10⁻⁵（n = 25），52周龄MWF大鼠为0.0027±0.00036（n = 36；P<0.0001）。用依那普利对12月龄蛋白尿MWF大鼠进行为期4周的治疗，使GSCA从0.0027±0.00036降至0.00139±0.00013（P = 0.0005）。同样，尿白蛋白排泄减少，依那普利给药前后分别平均为0.0051±0.0003和0.0036±0.0005毫克/毫渗摩尔每升（P = 0.0089）。同时，依那普利治疗降低了平均动脉血压（未治疗的MWF大鼠为144.6±6.5毫米汞柱，依那普利治疗的MWF大鼠为110.9±0.6毫米汞柱），并使肾小球滤过率从1.64±0.3毫升/分钟增加到3.58±0.3毫升/分钟（与基线相比，P = 0.0025）。总之，依那普利降低了蛋白尿MWF大鼠的GSCA，同时尿白蛋白排泄也有类似程度的减少。这些数据表明，ACE抑制剂有益的抗蛋白尿作用是由肾小球而非肾小管机制介导的。
