a Haemophilia PK & ADME , Novo Nordisk , Frederiksberg , Denmark.
b Department of Veterinary Disease Biology , University of Copenhagen , Frederiksberg , Denmark.
Ren Fail. 2018 Nov;40(1):640-648. doi: 10.1080/0886022X.2018.1533867.
Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD.
We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin-system (RAS).
The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice.
This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters.
慢性肾脏病（CKD）是一个全球性的健康问题，但目前的治疗方法只能减缓其进展。因此，需要更好地了解 CKD 的发病机制和新的治疗方法。肾毒性肾炎（NTN）模型具有研究 CKD 发病机制的潜力，因为它类似于人类 CKD。血管紧张素 II 受体阻滞剂（ARB）或血管紧张素转换酶抑制剂（ACE I）的经典治疗方法已在 CKD 中显示出临床效果。
我们通过研究功能和组织病理学变化，在 11 周内对 NTN 模型中的疾病发展进行了特征描述。我们在 NTN 模型中测试了 15 和 30mg/kg/天依那普利和氯沙坦的剂量，以研究抑制肾素-血管紧张素系统（RAS）的效果。
NTN 模型在第 6-7 天出现白蛋白尿峰值，系膜扩张（ME）、肾纤维化、炎症和铁积累在第 42 天达到峰值。然而，白蛋白尿、ME、肾纤维化和炎症在第 77 天仍显著存在，表明 NTN 模型可用于研究急性和慢性疾病阶段。依那普利和氯沙坦显著增强了肾小球滤过率（GFR），并降低了 NTN 诱导的小鼠肾病的白蛋白尿、ME、肾纤维化和炎症。
这是第一项研究，全面描述了小鼠 NTN 模型的慢性特征，并且抑制 RAS 途径对功能和形态参数具有显著效果。
