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

In previous studies, added parathyroid hormone-related protein (PTHrP) inhi bits whereas transfected PTHrP stimulates the proliferation of A10 aortic s mooth 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, an d whether they are altered in, 12-wk-old spontaneously hypertensive rats (S HR) as compared to normotensive Wistar-Kyoto (WKY) rats, SHR cells grew fas ter than WKY cells. PTHrP transcript was increased in SHR-derived cells whe reas 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) DNA, which abolished PTHrP mRNA, decreased WKY but increased SHR cell prol iferation. Added PTHrP(1-36) (1-100 pM) decreased WKY and increased SHR cel l proliferation, Additional studies indicated that the preferential couplin g of PTH1-R to G-protein Gi was responsible for the proliferative effect of exogenous PTHrP in SHR cells. Moreover, PTHrP was detected in the nucleolu s of a fraction of WKY and SHR renal SMC, in vitro as well as in situ, sugg esting that the nucleolar translocation of PTHrP might be involved in the p roliferative effects of endogenous PTHrP. In renovascular SMC, added PTHrP is antimitogenic, whereas endogenously produced PTHrP is mitogenic, These p aradoxical effects of PTHrP on renovascular SMC proliferation appear to be reversed in the SHR model of genetic hypertension, A new concept emerges fr om these results, according to which a single molecule may have opposite ef fects on VSMC proliferation under physiological and pathophysiological cond itions.-Mass-felder, T., Taesch, N., Endlich, N., Eichinger, A., Escande, B ., Endlich, K., Barthelmebs, M., Helwig, J.-J. Paradoxical actions of exoge nous and endogenous parathyroid hormone-related protein on renal vascular s mooth muscle cell proliferation: reversion in the SHR model of genetic hype rtension.