Sharkovska Yuliya, Kalk Philipp, von Websky Karoline, Relle Katharina, Pfab Thiemo, Alter Markus, Fischer Yvan, Hocher Berthold
Institute for Nutritional Science, University of Potsdam, Germany.
Clin Lab. 2011;57(7-8):507-15.
Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure.
Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested.
Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67% mortality in vehicle-treated rats, but only 20% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case).
The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
急性肾损伤（AKI）以及慢性肾衰竭都与极高的死亡率/发病率相关。然而，迄今为止，尚无药物被批准用于治疗急性肾衰竭，仅有少数药物被批准用于治疗慢性肾脏病（CKD）。我们分析了中性内肽酶（NEP）/内皮素转化酶（ECE）抑制剂SLV338在急性肾衰竭以及慢性肾衰竭动物模型中的作用。
通过切除雄性Wistar大鼠一侧肾脏并夹闭另一侧肾脏55分钟诱导急性肾衰竭。连续输注SLV338（总剂量：4.9mg/kg）或赋形剂2小时（在夹闭前20分钟开始）。假手术动物作为对照。在基线以及肾缺血再灌注后第2天和第8天测量血浆肌酐。通过使用L-NAME（每天50mg/kg，添加到饮用水中持续4周）造成一氧化氮缺乏，诱导雄性Sprague Dawley大鼠发生高血压肾损伤。一组在相同时间段内用SLV338（每天30mg/kg，与食物混合）治疗。每周监测收缩压。在研究结束时，收集尿液和血液样本并摘取肾脏。
急性肾缺血再灌注导致血浆肌酐升高5倍（第2天），在用SLV338治疗的动物中，这种升高显著减轻了50%以上（p<0.05）。肾衰竭在接受赋形剂治疗的大鼠中伴有67%的死亡率，但在SLV338治疗后仅为20%（与假手术对照组相比，p = 0.03）。长期给予L-NAME导致高血压、尿白蛋白排泄、肾小球硬化、肾动脉重塑以及肾间质纤维化。用SLV338治疗并未显著影响血压，但消除了肾组织损伤（间质纤维化、肾小球硬化、肾动脉重塑，每种情况与L-NAME组相比，p<0.05）。
双重ECE/NEP抑制剂SLV338可保护肾功能并降低严重急性缺血性肾衰竭的死亡率。此外，在L-NAME治疗的大鼠中，联合抑制ECE/NEP以血压非依赖性方式预防高血压肾组织损伤。
