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Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat

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Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat J Am Soc Nephrol 13: 639–648, 2002 Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat THIERRY MASSFELDER,*1 NATHALIE TAESCH,*†1 SAMUEL FRITSCH,* ANNE EICHINGER,* MARIETTE BARTHELMEBS,* ANDREW F. STEWART,† and JEAN-JACQUES HELWIG* *Section of Renovascular Pharmacology and Physiology (INSERM-ULP), University Louis Pasteur School of Medicine, Strasbourg, France; and †Division of Endocrinology and Metabolism, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Abstract. These studies examine whether PTHrP(1-36), a va- 23% and PTHrP(1-36)–induced vasodilation, which is de- sodilator, modulates BP and renal vascular resistance (RVR) in pressed in SHR, was restored and a vasoconstrictory response spontaneously hypertensive rat (SHR). Within the kidney of to PTH(3-34), a PTH1R antagonist, was revealed. These ef- normotensive rats, PTHrP(1-36) was enriched in vessels. In fects were not observed in control SHR treated with empty vessels of SHR, PTHrP was upregulated by 40% and type 1 plasmid. BP remained unchanged, and plasma renin activity PTH receptor (PTH1R) was downregulated by 65% compared increased by 60%. Thus, in SHR renal vessels, a reduced with normotensive rats. To investigate the role of endogenous number of PTH1R contributes to the high RVR, despite the PTHrP in the regulation of BP and RVR, SHR were subjected higher expression of vasodilatory PTHrP. Moreover, these to somatic human (h)PTH1R gene delivery. Three weeks after studies provide evidence for a direct link between the density a single intravenous injection of pcDNA1.1 plasmid containing of PTH1R and plasma renin activity, which might be respon- the hPTH1R gene under the control of the cytomegalovirus sible for the absence of effect of PTH1R gene delivery on BP promoter, hPTH1R mRNA was detected in all of the main in SHR. Overall, PTHrP significantly contributes to the ho- organs. Within the kidney, the transgene was enriched in meostasis of renal and systemic hemodynamics in SHR. vessels. In the isolated perfused kidney, RVR was reduced by Initially discovered as a tumor-derived humoral factor that onic development, and cell proliferation, apoptosis, and causes humoral hypercalcemia of malignancy, parathyroid hor- differentiation. mone-related protein (PTHrP) is now primarily considered to A number of recent findings prompted us to explore the role be a locally active polyhormone, ubiquitously produced of endogenous PTHrP in the regulation of renal hemodynamics throughout the normal body and endowed with cytokine- and in an animal model of genetic hypertension. First, transgenic growth hormone-like properties. Indeed, nascent PTHrP is mice that selectively overexpress PTHrP or the PTH1R in posttranslationally processed to a family a peptides, including smooth muscle exhibit a cardiovascular phenotype, including a PTHrP(1–36) (the PTH-like part of the molecule), PTHrP(38– decrease of BP (6,7). However, whether endogenous PTHrP 94) and PTHrP(107–139), each having its own biologic activ- modulates regional hemodynamics, including renal hemody- ities and receptors (1). The type 1 PTH receptor (PTH1R) (2) namics has not been clarified by these studies. Second, in both binds both PTHrP(1–36) and PTH(1–34), owing to structural human and animal studies, the renovascular system appeared to homologies existing between both peptides. The list of the be a privileged target of the vasodilatory properties of exoge- possible physiologic roles for PTHrP is continuously growing nous PTHrP(1–36), both in vitro an in vivo (8,9–13). In these (1,3–5). PTHrP is a regulator of transepithelial calcium trans- studies, PTHrP not only decreased renal vascular resistance port, vascular and extravascular smooth muscle tone, embry- (RVR) and increased GFR, but also appeared to be a potent stimulator of renin release by direct interaction with juxtaglo- merular cells (11). However again, a role for renovascular 1Thierry Massfelder and Nathalie Taesch participated equally in this work. PTHrP in the regulation of renal hemodynamics has not been Received June 12, 2001. Accepted August 21, 2001. sought in these studies. Finally, in terms of genetic hyperten- Correspondence to: Dr. Jean-Jacques Helwig, Pharmacologie & Physiologie sion, the spontaneously hypertensive rat (SHR) remains the Re´novasculaires, (Equipe Mixte INSERM-ULP 0015), 11, rue Humann, Baˆtiment most widely used animal model of primary hypertension (14). 4, 1er e´tage, F67085 Strasbourg Cedex, France. Phone: 333-90-24-34-54; Fax: 333-90-24-34-59; E-mail: [email protected] Genetically determined renal mechanisms play a major role in 1046-6673/1303-0639 the development of primary hypertension in both humans and Journal of the American Society of Nephrology SHR (14). The expression of PTHrP gene in blood vessels has Copyright © 2002 by the American Society of Nephrology been documented to be increased by vasoconstrictor agents and 640 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 639–648, 2002 mechanical forces (15,16). In the same vein, PTHrP transcript 1-36 region of the peptide (Peninsula Laboratories Ltd, St. Helens has also been shown to be upregulated in the aorta in experi- Merseyside, England). Results were expressed as pg PTHrP(1– Ϫ1 mental (17) as well as genetic hypertension (18). Whether the 36)·mg protein. vasoactivity of PTHrP(1–36) is altered in genetic hypertension has not been explored in these studies. In an earlier study, we Semiquantitative Reverse Transcriptase-PCR Analysis provided initial evidence for a marked decrease of PTHrP(1- for PTH1R Transcript 36)–induced vasodilation in the isolated perfused kidney of Total RNA of isolated renal vessels was prepared by the Tri- SHR (19). Overall, the central question as to whether vascular Reagent method according to the protocol of the manufacturer (Sig- PTH1R and PTHrP play a role in the modulation of renal as ma-Aldrich, St. Quentin Fallavier, France). Reverse transcription (RT) was performed on 4 ␮g (PTH1R) or 1.5 ␮g glyceraldehyde well as systemic hemodynamics in genetically hypertensive phosphodehydrogenase (GAPDH) denaturated RNA using moloney rats has not yet been tackled. murine leukemia virus reverse transcriptase (Perkin Elmer, Roissy, Therefore, this study had two goals: first, to examine ␮ France) and nonspecific P(dT)15 primer (2 M) at 37°C for 1 hr. PCR whether the expression of PTHrP and PTH1R are altered in the of the cDNA solutions was performed in the presence of specific renal vasculature of SHR, and second, to determine whether sense and antisense primers of PTH1R (13) or GAPDH (25). Con- endogenous vascular PTHrP plays a significant role in the centrations of PTH1R primers (50 pM) and GAPDH primers (4.4 pM) modulation of systemic and renal hemodynamics in these an- were adjusted in preliminary experiments to obtain similar product imals. PTH1R indeed appeared to be downregulated, and amplification despite the different abundance of transcripts. The PCR PTHrP upregulated in renal vessels of SHR, raising the ques- was run for 24 cycles by repeating denaturation at 94°C for 1 min, tion of whether a low expression of PTH1R could be respon- annealing at 60°C for 1 min, and polymerization at 72°C for 1 min in sible for the high BP and RVR in SHR. Recent studies have the presence of Taq polymerase (Sigma-Aldrich). The last cycle was followed by an additional incubation at 72°C for 8 min. The PCR demonstrated the potential of peripheral delivery of naked products were size fractionated by a 2% agarose gel electrophoresis. DNA coding for vasodilators to reduce BP in SHR (20–23). To PCR products were identified by their expected size of 817 bp investigate the role of endogenous PTHrP in the regulation of (PTH1R) and 415 bp (GAPDH). systemic and renal hemodynamics in SHR, these studies prompted us to ask whether a replenishment of the PTH1R Western Blot Analysis for the Rat PTH1R pool in peripheral and renal vessels by direct delivery of the The expression of PTH1R protein in 12-wk-old WKY and SHR human PTH1R (hPTH1R) gene would decrease RVR and renal vessels was evaluated by Western blot analysis as compared systemic BP in SHR. with COS7 cells taken as a negative control. Freshly isolated renal arteries were homogenized in homogenizing buffer consisting of 20 Materials and Methods mM Tris-HCl, 10% glycerol, 100 mM NaCl, 2 mM PMSF, 2 mM Animals EDTA, 2 mM ethyleneglycotetraacetic acid, 10 mM sodium or- ␮ Ϫ1 ␮ Ϫ1 All animal studies were approved by and in compliance with thovanadate, 10 g·ml , leupeptin and 10 g·ml aprotinin. After guidelines of the European Community and the French Government 30-min centrifugation at 30,000 g, the pellets were incubated at 4°C (Ministry of Agriculture) concerning the animal experimentation. during 30 min in homogenizing buffer complemented with 1% NP-40, Nine or 12-wk-old SHR and Wistar Kyoto (WKY) rats (Iffa-Credo, 0.1% sodium dodecyl sulfate (SDS) and 1% deoxycholate and cen- l‘Arbresle, France) with free access to standard food and water were trifuged for 30 min at 30,000 g, and the supernatant was used for used. SHR are in a prehypertensive state up to 4 wk. Mean BP in Western blot analysis. COS-7 cells were grown and lysed exactly as 12-wk-old SHR was 184 Ϯ 3 mmHg (n ϭ 8) as compared with 123 described before (26). Protein concentrations were determined accord- Ϯ 4 mmHg (n ϭ 5) in normotensive WKY rats. ing to the method of Lowry et al. (27) with bovine serum albumin as standard. Samples were subjected to SDS-polyacrylamide gel electro- phoresis exactly as described before (26). Isolation of Rat Intrarenal Arteries Twelve-week-old WKY and SHR were anesthetized with ether and pcDNA1.1-hPTH1R Plasmid DNA Preparation decapitated.
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