Abstract The collecting duct (CD), the terminal part of the nephron, plays a pivotal role in fine-tuning urinary water and Na+ excretion to maintain homeostatic control of body fluid volume and blood pressure. This is the nephron site where the transport processes are highly regulated by hormonal factors such as vasopressin and aldosterone. Recently, we and others have discovered (pro)renin receptor (PRR) and PPARγ as important regulators of the transport processes in the CD. In this regard, deletion of PRR in the nephron or the CD induces diabetes insipidus and activation of PRR in the CD cells stimulates expression or activity of AQP2 and/or ENaC. The action of PRR in the CD is mediated in part by releasing soluble PRR (sPRR). On the other hand, emerging evidence shows that nuclear receptors play an important role in regulation of fluid balance beyond the energy control. This is highlighted by the fluid-retaining action of PPARγ in the CD, which underlies thiazolidinedione- induced fluid retention, a major off-target effect of the antidiabetic agents. In preliminary studies, we discovered that site-1 protease (S1P) represents a predominant protease responsible for the cleavage process to produce sPRR. Moreover, both PRR and S1P appear to be direct target genes of PPARγ in the CD. Based on these observations, we hypothesize that PPARγ transcriptionally upregulates expression of PRR and S1P in the CD, leading to enhancement of local sPRR production and activation of intrarenal RAS, ultimately increasing fluid reabsorption and expanding plasma volume. To test this hypothesis, we propose the following 3 specific aims: (1) to define PPARγ as a transcriptional activator of PRR gene in the CD cells, (2) to test the role of S1P- derived sPRR in mediating Rosi-induced fluid retention, (3) to test the dependence of PRR/sPRR signaling on binding to prorenin/renin during Rosi treatment. Together, new information resulted from this proposal is expected to offer new insight into the newly discovered PRR-dependent pathway in the CD for homeostatic control of fluid balance.