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Am J Physiol Cell Physiol (January 23, 2002). doi:10.1152/ajpcell.00561.2001
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Articles in PresS, published online ahead of print January 23, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00561.2001
Submitted on November 26, 2001
Accepted on January 22, 2002

A Novel Regulation Of Adrenomedullin Receptor By PDGF In Mesangial Cells- Role Of Receptor Activity Modifying Protein-3

Wojciech Nowak1, Narayanan Parameswaran1, Carolyn S Hall1, Nambi Aiyar2, Harvey V Sparks1, and William S Spielman1*

1 Physiology, Michigan State University, East Lansing, Michigan, USA
2 Cardiovascular biology, GlaxoSmithKline pharmaceuticals, King of Prussia, Pennsylvania, USA

* To whom correspondence should be addressed. E-mail: spielman{at}msu.edu.

Receptor activity modifying protein-3 (RAMP-3) has been shown to complex with the calcitonin receptor-like receptor establishing a functional receptor for adrenomedullin (AM). AM exhibits potent anti-proliferative and anti-migratory effects on rat mesangial cells (RMC). In this study we investigated the effect of platelet-derived growth factor (PDGF) on RAMP-3 expression in RMC. We show here that PDGF-BB stimulates RAMP-3 mRNA expression in a concentration-dependent manner. Pre-treatment with actinomycin-D and {alpha}-amanitin demonstrates that this effect is independent of new RNA synthesis. Furthermore, PDGF increased the half-life of RAMP-3 mRNA from 66.5 to 331.6 min. Using selective inhibitors, our results also indicate that the increase in RAMP-3 mRNA is MAPKK/MAPK and p38 MAPK dependent. PDGF also caused a corresponding elevation in membrane-associated RAMP-3 protein. Associated with this increase, PDGF pretreatment led to a significantly higher AM-mediated adenylate cyclase activity, suggesting a functional consequence for the PDGF-induced increase in RAMP-3 expression. Taken together, these data identify PDGF-dependent regulation of RAMP-3 expression as a possible mechanism for modulating mesangial cell's responsiveness to AM.






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