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Abstract

A number of observations prompted us to explore the PTHrP system in renal vessels of SHR. First, the kidney is acknowledged as a major target of the dilatory effect of PTHrP in human and animal studies. Second, genetically determined renal mechanisms, including high renal vascular resistance (RVR), play a major role in the development of primary hypertension. Third, PTHrP mRNA has been shown to be upregulated in the aorta in genetic, as well as experimental hypertension. Finally, we reported earlier that the vasodilatory effect of PTHrP was reduced in SHR isolated perfused kidney (IPK), as compared to normotensive animals.

We now report that in small arteries isolated from kidney of 12-week-old SHR, immunoreactive PTHrP expression was increased by ~40 %, while both PTH1 receptor (PTH1R) mRNA (RT-PCR) and protein (Western blot) were decreased by ~60-80 %, as compared to age-matched WKY rats (p<0.05). These observations suggested potential beneficial effects of somatic human (h)PTH1R gene delivery to decrease RVR in SHR. To test this possibility, the hPTH1R DNA (1.9 kb), under the control of the cytomegalovirus promoter in the pcDNA1.1 vector was generated. The naked DNA construct (0.5mg) was delivered into SHR via a single intravenous injection. Control-treated SHR received 0.5mg empty vector. Three weeks after plasmid delivery, the expression of hPTH1R mRNA was identified by RT-PCR analysis in all main organs, including hearth, brain, aorta, liver and lungs. In kidney, hPTH1R transcipt was preferentially expressed in isolated intrarenal arteries as compared to total kidney. In IPKs, a submaximal concentration of PTHrP(1-36) (10 nM) decreased the preconstrictiopn induced by 10 μM phenylephrine, by 19±11 % in control-treated SHR (n=5, p>0.05) This vasodilatory effect was increased to 54±8 % (n=5, p<0.05) in PTH1R-transfected SHR. PTH1R gene delivery, also decreased basal RVR of the IPK from 7.2±0.2 (n=9) in control-treated to 5.2±0.3 mmHg min g ml-1 (n=13) in hPTH1R-transfected (p<0.05). Finally, infusion of 40nM PTHrP(3-36), an antagonist of PTH1R, had no effect in control-treated SHR, but displayed vasoconstrictory effect, increasing basal RVR in IPK by ~13 % (n=4, p<0.05) in PTH1R-transfected SHR.

Collectively, these results strongly suggest that downregulation of PTH1R contributes to high RVR in SHR, despite the upregulation of its endogenous ligand. Replenishment of renal vascular pool of PTH1R by somatic gene delivery decreased RVR, owing to endogenous vasodilatory PTHrP. Thus, in SHR, endogenous PTHrP system modulates renal tonus, at least in vitro.

spontaneously hypertensive rats, parathyroid hormone-related protein (PTHrP), renal vessels
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© American Journal of Hypertension, Ltd. 2001
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