PARATHYROID HORMONE-RELATED PEPTIDE (PTHrP) INTERACTIONS WITH RENAL RENIN AND EDRF SYSTEMS

Abstract

PTHrP, the primary causative agent of the hypercalcemia associated with humoral malignancy, is so-named for its ability to act as a PTH agonist in kidney and bone. Like PTH, PTHrP is also hypotensive and vasorelaxant. But, unlike PTH, PTHrP siiRNA has been localized in normal fetal and adult tissues including vascular tissue. Thus, PTHrP may serve as a local regulator of the hemodynamic of developping and adult kidney. In light of this possibility we demonstrated earlier the presence of receptors responsive to PTHrP in preglomerular vessels and its vasorelaxant action in the isolated perfused kidney (IPK) of rat. In this work, we show that 125nM PTHrP increased renin release (RR) from non filtering IPK of rat perfused at constant flow and stabilized pressure (70 mm Hg) by 161%. PTHrP reversed the inhibiting effect of hypercalcic media (2mM Ca2+) and 20nM BAY-K8644 (Ca channel opener). In rabbit IPK preconstrieted with norepinephrine, 1μM Nw-Nltro-L-Arg Benzyl Ester (NABE), an inhibitor of EDRF synthesis decreased by 80-90% the renal relaxation in response to 10μM acetylcholine. Parallely, NABE decreased by 20 to 40% the relaxation in response to 87nM of PTHrP.Conclusion: 1) PTHrP stimulates RR independently from macula densa and baroreceptor mechanisms by a Ca-dependent process; 2) renal vasodilatation in response to PTHrP probably involves in addit ion to cAMP, an EDRF-dependent process. Together with the presence of PTHrP mRNA in smooth muscle cells shown in other respects, these results support the view that PTHrP contributes locally to renal blood flow regulation.