Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats.

Abstract

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.

• Authors: Bing Dai, Yawei Liu, Changlin Mei, Lili Fu, Xishan Xiong, Yan Zhang, Xuefei Shen, Zhenhao Hua
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 119 Issue 8 Pg. 323-33 (Jul 09 2010) ISSN: 1470-8736 [Electronic] England
• PMID: 20507283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, rat
• Chemokine CCL2
• Hypoglycemic Agents
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Transforming Growth Factor beta1
• Rosiglitazone

Topics

• Animals
• Chemokine CCL2 (biosynthesis, genetics)
• Disease Models, Animal
• Disease Progression
• Drug Administration Schedule
• Drug Evaluation, Preclinical
• Hypoglycemic Agents (therapeutic use)
• Male
• PPAR gamma (agonists)
• Polycystic Kidney Diseases (drug therapy, metabolism, pathology)
• RNA, Messenger (genetics)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Rosiglitazone
• Survival Analysis
• Thiazolidinediones (therapeutic use)
• Transforming Growth Factor beta1 (biosynthesis, genetics)