TY - JOUR
T1 - Parathyroid hormone-related protein detection and interaction with NO and cyclic AMP in the renovascular system
AU - Massfelder, Thierry
AU - Stewart, Andrew F.
AU - Endlich, Karlhans
AU - Soifer, Neil
AU - Judes, Clément
AU - Helwig, Jean Jacques
N1 - Funding Information:
(ENSFRM) grant CRE 920203 and CJF 9409, the French Ministry of Higher Education EA1314, and by the Department of Veterans Affairs, West Haven, CT, USA. We thank Mrs. Elisabeth Friedmann, Jeanine Krill and Suzanne Wendling for technical assistance, and Mrs. Sylvie Rothhut and Danièle Kuhlwein for manuscript preparation.
PY - 1996/11
Y1 - 1996/11
N2 - 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 ihibition of 2.5 x 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 antifactor 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/guanylylcyclase 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.
AB - 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 ihibition of 2.5 x 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 antifactor 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/guanylylcyclase 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.
UR - https://www.scopus.com/pages/publications/0029906797
U2 - 10.1038/ki.1996.475
DO - 10.1038/ki.1996.475
M3 - Article
C2 - 8914026
AN - SCOPUS:0029906797
SN - 0085-2538
VL - 50
SP - 1591
EP - 1603
JO - Kidney International
JF - Kidney International
IS - 5
ER -