Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats
Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats
复制标题
罗格列酮可减轻 Han:SPRD 大鼠多囊肾病的发展并延长其生存期
DOI：
10.1042/cs20100113
复制
发表时间：
2010-10-01
期刊：
影响因子：
6
通讯作者：
Hua, Zhenhao
中科院分区：
文献类型：
--
作者：
Dai, Bing;Liu, Yawei;Hua, Zhenhao
尽管吡格列酮是一种PPAR-γ(过氧化物酶体-增殖物激活受体-γ)激动剂，已被证明通过不同的机制延长了两种快速进展的PKD 1(多囊肾病1)基因敲除小鼠的存活时间，但由于观察期较短，这些研究缺乏关于治疗潜力和长期安全性的数据。在本研究中，我们使用了另一种有效的PPAR-γ激动剂罗格列酮来治疗HAN：SPRD大鼠，这是一种缓慢进展的ADPKD(常染色体显性遗传性PKD)动物模型，并证实短期治疗能够延缓肾囊肿的进展，保护肾功能，这可能与下调异常激活的β-连环素信号通路及其抗炎和抗纤维化作用有关。长期给药可显著延长HAN：SPRD大鼠的存活时间。此外，肾功能正常的大鼠的早期治疗比延迟治疗的结果更好，而对肾功能轻度受损的大鼠开始治疗仍然可以保护肾功能。罗格列酮的疗效依赖于持续给药；停药会导致有效治疗的大鼠肾功能加速恶化，并使其存活时间缩短至未经治疗的状态。长期给药导致心脏增大，可能是由于罗格列酮介导的钠重新吸收。综上所述，罗格列酮能有效延缓HAN-SPRD大鼠肾脏疾病的进展，保护肾功能，但其引起心脏增大的不良反应也应密切关注。
Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd 1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.