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Paradoxical actions of exogenous and endogenous parathyroid hormone-related protein on renal vascular smooth muscle cell proliferation: reversion in the SHR model of genetic hypertension

Section of Renovascular Pharmacology and Physiology (INSERM-ULP), University Louis Pasteur School of Medicine, Strasbourg, France

¹Correspondence: Pharmacologie et Physiologie Rénovasculaires (Equipe INSERM 0015-Equipe MENRT 2307), 11, rue Humann, Bâtiment 4, 1^er étage, F67085 Strasbourg Cédex, France. E-mail: Jean-Jacques.Helwig{at}pharmaco-ulp.u-strasbg.fr

In previous studies, added parathyroid hormone-related protein (PTHrP) inhibits whereas transfected PTHrP stimulates the proliferation of A10 aortic smooth muscle cells by nuclear translocation of the peptide. In the present studies, we asked whether these paradoxical trophic actions of PTHrP occur in smooth muscle cells (SMC) cultured from small intrarenal arteries of, and whether they are altered in, 12-wk-old spontaneously hypertensive rats (SHR) as compared to normotensive Wistar-Kyoto (WKY) rats. SHR cells grew faster than WKY cells. PTHrP transcript was increased in SHR-derived cells whereas PTH1 receptor (PTH1R) transcripts were similar in both cell lines. In both strains of cells, stable transfection with human PTHrP(1–139) cDNA did not further induce proliferation, suggesting maximal effect of endogenous PTHrP in wild cells. In contrast, transfection with antisense hPTHrP(1–139) cDNA, which abolished PTHrP mRNA, decreased WKY but increased SHR cell proliferation. Added PTHrP(1–36) (1–100 pM) decreased WKY and increased SHR cell proliferation. Additional studies indicated that the preferential coupling of PTH1-R to G-protein G_i was responsible for the proliferative effect of exogenous PTHrP in SHR cells. Moreover, PTHrP was detected in the nucleolus of a fraction of WKY and SHR renal SMC, in vitro as well as in situ, suggesting that the nucleolar translocation of PTHrP might be involved in the proliferative effects of endogenous PTHrP. In renovascular SMC, added PTHrP is antimitogenic, whereas endogenously produced PTHrP is mitogenic. These paradoxical effects of PTHrP on renovascular SMC proliferation appear to be reversed in the SHR model of genetic hypertension. A new concept emerges from these results, according to which a single molecule may have opposite effects on VSMC proliferation under physiological and pathophysiological conditions.—Massfelder, T., Taesch, N., Endlich, N., Eichinger, A., Escande, B., Endlich, K., Barthelmebs, M., Helwig, J.-J. Paradoxical actions of exogenous and endogenous parathyroid hormone-related protein on renal vascular smooth muscle cell proliferation: reversion in the SHR model of genetic hypertension.

Key Words: mitogenesis • intracrine • nucleolus

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