The proxisomal proliferator activated receptor subtype gamma (PPARgamma) ligands, synthetic insulin sensitizing thiazolidinedione compounds (TZD), are highly effective in treatment of type II diabetes. However, these drugs are associated with fluid retention, representing early evidence for involvement of PPARgamma in fluid homeostasis. Using RT-PCR and microdissection, we demonstrate predominant expression of PPAR? mRNA in inner medullary collecting duct (IMCD), a critical site for regulation of fluid reabsorption and blood pressure. Furthermore, PPARgamma activators stimulate renal expressions of various transporters such as aquaporins 2 and 3, NKCC2, alpha-1 subunit of Na-K ATPase in vivo and enhance cell surface ENaCa in human collecting duct (CD) cells in vitro. Based on these observations, we speculate that PPARgamma may play an important role in the control of salt and water homeostasis through influence on the CD function. Given the facts that PPARgamma is expressed in various cell types throughout the body and systemic deletion of PPARgamma gene produces lethality, Cre-loxP system will be required to address the function of CD PPARgamma. The PI already has PPARgamma floxed mice received from Dr. Frank Gonzalez at NIH and CD Cre expressing transgenic mice received locally from Dr. Donald Kohan. This proposal will generate mice with CD-specific deletion of PPARgamma gene (termed CD PPAR? KO) by genetic cross between PPAR? floxed and AQP2-CreTag mice, and further characterize the phenotype related to fluid homeostasis and blood pressure regulation. To address the question that TZD-induced fluid retention may involve the whole kidney rather than a specific cell type, we will take an alternative approach to delete PPARgamma in the entire kidney (termed Renal PPARgamma KO) using an ultrasound-microbubble-mediated Cre-LoxP system. This proposal has the following three specific aims: 1) to create mice with CD-specific knockout of PPARgamma, 2) to analyze phenotype of CD PPAR? KO mice, and 3) to create renal-specific knockout of PPARgamma using ultrasound-microbubble-mediated Cre-LoxP system. New information provided by this proposal is expected to provide insights into the roles of PPARgamma in regulation of fluid balance and in mediation of the side effects of TDZ.
| Yang, Tianxin (2006) Kidney-specific gene targeting: insight into thiazolidinedione-induced fluid retention. Nephrology (Carlton) 11:201-6 |
| Yang, Tianxin; Zhang, Aihua; Honeggar, Matthew et al. (2005) Hypertonic induction of COX-2 in collecting duct cells by reactive oxygen species of mitochondrial origin. J Biol Chem 280:34966-73 |
