Prostaglandin receptors: their role in regulating renal function.

ABSTRACT

Renal cyclooxygenase-1 and cyclooxygenase-2 actively metabolize arachidonate to metabolism five primary prostanoids prostaglandin E2, prostaglandin F2a, 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 their activation are being characterized. The FP, TP, and EP1 receptors preferentially couple to increased cell Ca2+. EP2, EP4, DP, and IP receptors stimulate cyclic adenosine monophosphate, whereas the EP3 receptor preferentially couples to Gi, inhibiting cyclic adenosine monophosphate generation. EP1 and EP3 messenger RNA expression predominate in the collecting duct and thick limb, respectively, where their stimulation reduces sodium chloride and water absorption, promoting natriuresis and diuresis. Interestingly, only a mild change in renal water handling is seen in the EP3 receptor knockout mouse. Although only low levels EP2 receptor messenger RNA are detected in kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor display salt-sensitive hypertension, suggesting it also plays an important role in salt excretion. In contrast, EP4 messenger RNA is readily detected in the glomerulus where it may contribute to the regulation of renin release and decrease glomerular resistance. TP receptors are also highly expressed in the glomerulus, where they may increase glomerular vascular resistance. The IP receptor messenger RNA is most highly expressed in the afferent arteriole and it may also modulate renal arterial resistance and renin release. At present there is little evidence for DP receptor expression in the kidney. Together these receptors act as physiologic buffers that protect the kidney from excessive functional changes during periods of physiologic stress. Loss of the combined effects of these receptors contributes to the side effects seen in the setting of nonsteroidal anti-inflammatory drug administration, whereas selective antagonists for these receptors may provide new therapeutic approaches in disease.