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Cell-Specific Expression of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene in Kidney from Kidney-Specific and Ubiquitous Promoters¹

Department of Medicine (N.A., A.A., G.N.H., D.G.) and Physiology (H.S.L., M.Y.K., G.N.H., J.H.W., D.G.), and Anatomy and Cell Biology (H.W.), McGill University, and Calcium Research Laboratory (N.A., A.A., G.N.H., D.G.), Royal Victoria Hospital, Montreal, Quebec H3G 1Y6, Canada; and the Department of Oral Anatomy (N.A., H.O.), Niigata University School of Dentistry, 5274, 2-Bancho Gakkoucho-Dori, Niigata, 951 Japan

Address all correspondence and requests for reprints to: J. H. White, Department of Physiology, McIntyre Medical Sciences Building, Room 1109, McGill University, 3655 Drummond Street, Quebec H3G 1Y6, Canada. E-mail: jwhite{at}physio.mcgill.ca

The kidney is the major site of expression of the PTH/PTH-related peptide receptor (PTHR) gene. Previously we have shown that the PTHR gene is expressed from two promoters in kidney, an upstream kidney-specific promoter (P1) and a downstream promoter (P2) that is active in a wide variety of tissues. Here, we have used immunohistochemical and transcript-specific in situ hybridization techniques to map the expression of the PTHR gene and protein and to determine the distribution of P1- and P2-driven messenger RNAs in renal tissue. Immunohistochemical and immunoelectron microscopic analysis showed that PTHR protein is expressed on both basolateral and luminal membranes of proximal tubular epithelial cells, strongly suggesting a bipolar mode of action of PTH. Receptor protein also was detected on the surface of glomerular podocytes. Strikingly, immunoelectron microscopic analysis showed that endothelial cells of the peritubular vasculature, but not the glomerular vasculature, contain high levels of PTHR protein. We found that both P1 and P2 are expressed at moderate levels in both cortical and medullary epithelial cells of nephrons, correlating well with the immunohistochemical localization of PTHR protein. However, although abundant transcripts were detected in peritubular endothelial cells with P1-specific and coding sequence probes, P2-specific expression was not observed in these cells. These results provide evidence that the physiological effects of PTH- and/or PTH-related peptide on renal tubular function may be mediated not only through direct effects on epithelial cells but also indirectly through endothelial cell-based signaling. In addition to expression in vascular endothelial cells, high levels of P1-specific, but not P2-specific, PTHR messenger RNA were detected in vascular smooth muscle. Taken together, these experiments provide evidence for strong PTHR gene expression in renal vascular tissues. Moreover, given that previous studies have shown that P2, but not P1, is active in other tissues with an abundant vasculature, our results suggest that regulation of PTHR gene expression in renal vascular tissue is distinct from that of other organs.

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