Laboratory Investigation

Kidney International (1996) 50, 1591–1603; doi:10.1038/ki.1996.475

Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system

Thierry Massfelder, Andrew F Stewart, Karlhans Endlich, Neil Soifer, Clément Judes and Jean-Jacques Helwig

Laboratoire de Physiologie Cellulaire Rénale, Faculté de Médecine, Université Louis Pasteur, CJF INSERM 9409, Strasbourg, France; Division of Endocrinology, West Haven VA Medical Center, West Haven, Connecticut, USA; and I. Physiologisches Institut der Universität Heidelberg, Heidelberg, Germany

Correspondence: Dr Jean-Jacques Helwig, Laboratoire de Physiologie Cellulaire Rénale, Pavillon Poincaré, Hospices Civils, B.P. 426, F67091 Strasbourg Cedex, France.

Received 16 February 1996; Revised 3 May 1996; Accepted 17 June 1996.

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Abstract

Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system. The presence of parathyroid hormone-related protein (PTHrP) in human kidney vasculature and the signal transduction pathways stimulated during PTHrP-induced vasodilation of the rabbit kidney were investigated. Immunostaining of human kidney revealed the abundant presence of PTHrP in media and intima of all microvessels as well as in macula densa. In isolated perfused rabbit kidney preconstricted with noradrenaline, 10-5 M Rp-cAMPS, a direct inhibitor of protein kinase A, produced comparable inhibition of 2.5 times 10-7 M forskolin- and 10-7 M PTHrP-induced vasorelaxations. Renal vasorelaxation and renal microvessel adenylyl cyclase stimulation underwent comparable desensitization following exposure to PTHrP. Nitric oxide (NO)-synthase inhibition by L-NAME (10-4 M), NO scavenging by an imidazolineoxyl N-oxide (10-4 M) and guanylyl cyclase inhibition by methylene blue (10-4 M) decreased PTHrP-induced vasorelaxation by 27 to 53%, abolished bradykinin-induced vasorelaxation and did not affect forskolin-induced vasorelaxation. The effects of Rp-cAMPS and L-NAME were not additive on PTHrP-induced vasorelaxation. Damaging endothelium by treating the kidney with either anti-factor VIII-related antibody and complement, gossypol or detergent, did not affect PTHrP- or forskolin-induced vasorelaxations but reduced bradykinin-induced vasorelaxation by 53 to 92%. Conversely, endothelial damage did not alter the inhibitory action of L-NAME on PTHrP-induced vasorelaxation. In conclusion, PTHrP is present throughout the human renovascular tree and juxtaglomerular apparatus. Activation of both adenylyl cyclase/protein kinase A and NO-synthase/guanylyl cyclase pathways are directly linked to the renodilatory action of PTHrP in a way that does not require an intact endothelium in the isolated rabbit kidney.

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