G Protein–Coupled Prostanoid Receptors and the Kidney

▪ Abstract  Renal cyclooxygenase 1 and 2 activity produces five primary prostanoids: prostaglandin E2, prostaglandin F2α, prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators interact with a family of distinct G protein-coupled prostanoid receptors designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory effects on renal function. The intrarenal distribution of these prostanoid receptors has been mapped, and the consequences of their activation have been partially characterized. FP, TP, and EP1receptors preferentially couple to an increase in cell calcium. EP2, EP4, DP, and IP receptors stimulate cyclic AMP, whereas the EP3receptor preferentially couples to Gi, inhibiting cyclic AMP generation. EP1and EP3mRNA expression predominates in the collecting duct and thick limb, respectively, where their stimulation reduces NaCl and water absorption, promoting natriuresis and diuresis. The FP receptor is highly expressed in the distal convoluted tubule, where it may have a distinct effect on renal salt transport. Although only low levels of EP2receptor mRNA are detected in the kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2receptor exhibit salt-sensitive hypertension, suggesting that this receptor may also play an important role in salt excretion. In contrast, EP4receptor 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 near the glomerulus, in the afferent arteriole, where it may also dilate renal arterioles and stimulate renin release. Conversely, TP receptors in the glomerulus may counteract the effects of these dilator prostanoids and increase glomerular resistance. At present there is little evidence for DP receptor expression in the kidney. These receptors act in a concerted fashion as physiological buffers, protecting the kidney from excessive functional changes during periods of physiological stress. Nonsteroidal anti-inflammatory drug (NSAID)-mediated cyclooxygenase inhibition results in the loss of these combined effects, which contributes to their renal effects. Selective prostanoid receptor antagonists may provide new therapeutic approaches for specific disease states.