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Water deprivation enhances the inhibitory effect of natriuretic peptides on cAMP synthesis in rat renal glomeruli

¹National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752; ²Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029; and ³Department of Physiology, University of Extremadura, 10071 Cáceres, Spain

Submitted 2 March 2004 ; accepted in final form 27 April 2004

This study investigates the effect of water deprivation on the expression of atrial natiruretic peptide (ANP)_1-28 binding sites in rat kidney. Water deprivation increased the B_max of glomerular binding sites for ANP_1-28 and C-type natriuretic peptide (CNP)_1-22 without modifying their affinity, an effect that was prevented in the presence of C-atrial natriuretic factor (C-ANF), suggesting that natriuretic peptide receptor-C (NPR-C) binding sites might be enhanced. Our results indicate that ANP_1-28, CNP_1-22, and C-ANF inhibit cAMP synthesis directly stimulated by forskolin or by the physiological agonists histamine and 5-hydroxytryptamine. The inhibitory effect was found to be significantly greater in water-deprived rats than in controls. Our observations suggest that this effect must be attributed to the 67-kDa NPR-C-like protein, because the 67- and 77-kDa NPR-C-like proteins show high and low affinities for CNP_1-22, respectively, and the enhanced inhibitory effect of CNP on cAMP generation in water-deprived rats was detected at subnanomolar concentrations. In addition, using affinity cross-linking studies we have observed that water deprivation increases the expression of the 67-kDa NPR-C-like protein, and HS-142, which binds to NPR-A and the 77-kDa NPR-C-like but not the 67-kDa protein, reduced ligand internalization without affecting cAMP inhibition by ANP_1-28. Finally, we have found that ligand binding to the 67-kDa NPR-C-like protein is reduced by GTPS, suggesting that this receptor is associated with a G protein in renal glomeruli. The enhanced inhibitory role of natriuretic peptides on cAMP synthesis induced by water deprivation may influence glomerular function in the rat kidney.

C-type natriuretic peptide; C-atrial natriuretic factor; natriuretic peptide receptor-C