G protein-coupled prostanoid receptors and the kidney

Renal cyclooxygenase 1 and 2 activity produces five primary prostanoids: pr ostaglandin E-2, prostaglandin F-2 alpha, prostaglandin I-2, thromboxane A( 2), and prostaglandin D-2. These lipid mediators interact with a family of distinct G protein-coupled prostanoid receptors designated EP, FP, IP,TP, a nd DP, respectively, which exert important regulatory effects on renal func tion. The intrarenal distribution of these prostanoid receptors has been ma pped, and the consequences of their activation have been partially characte rized. EP, TP, and EP1 receptors preferentially couple to an increase in ce ll calcium. EP2, EP4, DP, and IP receptors stimulate cyclic AMP, whereas th e EP3 receptor preferentially couples to Gi, inhibiting cyclic AMP generati on. EP1 and EP3 mRNA expression predominates in the collecting duct and thi ck limb, respectively, where their stimulation reduces NaCl and water absor ption, promoting natriuresis and diuresis. The FP receptor is highly expres sed in the distal convoluted tubule, where it may have a distinct effect on renal salt transport. Although only low levels of EP2 receptor mRNA are de tected in the kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor exhibit salt-sensitive hy pertension, suggesting that this receptor may also play an important role i n salt excretion. In contrast, EP4 receptor mRNA is predominantly expressed in the glomerulus, where it may contribute to the regulation of glomerular hemodynamics and renin release. The IP receptor mRNA is highly expressed n ear the glomerulus, in the afferent arteriole, where it may also dilate ren al arterioles and stimulate renin release. Conversely, TP receptors in the glomerulus may counteract the effects of these dilator prostanoids and incr ease glomerular resistance. At present there is little evidence for DP rece ptor expression in the kidney. These receptors act in a concerted fashion a s physiological buffers, protecting the kidney from excessive functional ch anges during periods of physiological stress. Nonsteroidal anti-inflammator y drug (NSAID)-mediated cyclooxygenase inhibition results in the loss of th ese combined effects, which contributes to their renal effects. Selective p rostanoid receptor antagonists may provide new therapeutic approaches for s pecific disease states.