My long-term research interests are the roles of prostaglandins and other lipid-derived products in regulation of fluid metabolism and blood pressure. Prostaglandins are products of arichaidoninc acid via the activity of cyclooxygenase and a specific prostanoid synthase. Our early work revealed an important relationship between dietary salt intake and regulation of COX-2 expression in macula densa and renal medulla with low salt increasing COX-2 expression in cortex but high salt increasing it in renal medulla. We for the first time isolated and characterized a macula densa cell line from renal cortex of SV-40 T antigen transgenic mice using cell sorting technique. We demonstrate that low chloride stimulates prostaglandin release and COX-2 expression. Using COX-2 knockout mice, we demonstrate that COX-2 is critically important for renin response to low sodium intake. In parallel to the work on macula densa COX-2, we performed a series of studies to investigate the regulation and function of renal medullary COX-2. We have proved that hypertonicity has a direct stimulatory effect on COX-2 gene expression via reactive oxygen species-dependent activation of MAP kinase. More recently, we reported that intramedullary infusion of the COX-2 inhibitor NS-398 to Sprague-Dawley rats induced salt-sensitive hypertension, establishing an essential role of renal medullary COX-2 in stabilizing blood pressure during high salt intake.
PGE2 is a dominant prostaglandin produced in the kidney and is considered as an important player in the control of sodium balance and blood pressure. To date, three major forms of prostaglandin E synthase (PGES) have been cloned and characterized: membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). Among them, mPGES-1 is critically involved in pain and inflammatory responses and viewed as an alternative target for the development of the next generation of analgesics. In recent years, we conducted a series of studies to investigate the physiological function of mPGES-1. We found that within the kidney, mPGES-1 predominates in the distal nephron where its expression is highly inducible by salt loading; mice lacking mPGES-1 exhibit blunted natriuretic response to acute and chronic salt loading, in parallel with suppressed nitric oxide production (Jia Z et al. Cir. Res. 2006). These mice also exhibit an exaggerated hypertensive response to angiotensin II infusion and mineralocorticoid excess. These results suggest that mPGES-1-derived PGE2 may play an important role in buffering the sodium-retaining and pro-hypertensive action of the renin-angiotensin-aldosterone system. In addition, we discovered that mPGES-1-derived PGE2 mediates diuretic response to water loading and lithium treatment.
PPARγ is a ligand-activated transcription factor promoting adipogenesis and energy storage.Our previous study demonstrates abundant expression of PPARγ in the distal nephron. Using conditional KO mice, we found that collecting duct PPARγ mediates thiazolidinedione (TZD)-induced fluid retention, a major side effect of the antidiabetic drug (Zhang et al. Proc Natl Acad Sci U S A. 102:9406-11). To address the paradox of lack of hypertension in TZD-induced fluid retention, we investigated a potential blood pressure lowering effect of vascular PPARγ. Using conditional KO mice, we demonstrate that endothelial but not smooth muscle PPARγ contributes to the blood pressure lowering effect of TZDs. Moreover, endothelial PPARγ regulates microvascular transport of fluid together with fatty acids only in the adipose tissue via increasing capillary permeability in the local environment. The coupling of the transport processes for movement of fluid and nutrients from the circulation to the adipose tissue provides a teleological explanation of why this energy regulator can have a profound effect on fluid metabolism. More recent data show that PPARγ regulates circadian rhythms of blood pressure and heart rate (Wang N et al. Cell Metabolism 2008) as well as behavior and metabolism through a direct interaction with the core molecular clock in the peripheral tissues. It has been well established that disruption of circadian rhythms lead to metabolic syndrome as well as salt-sensitive hypertension. Together, our data indicate that PPARγ controls energy homeostasis via integrating fluid and fatty acid metabolism and circadian rhythms. We are exploring the potential role of dysregulation of PPARγ in the cardio-renal system in obesity that may lead to sodium and fluid retention and thereby increased blood pressure.
