Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats.
Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (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.
Dai
Bing
B
Kidney Institute of PLA, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Liu
Yawei
Y
Mei
Changlin
C
Fu
Lili
L
Xiong
Xishan
X
Zhang
Yan
Y
Shen
Xuefei
X
Hua
Zhenhao
Z
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000077154:Rosiglitazone; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone