CELL-SPECIFIC EXPRESSION OF THE PARATHYROID-HORMONE (PTH) PTH-RELATEDPEPTIDE RECEPTOR GENE IN KIDNEY FROM KIDNEY-SPECIFIC AND UBIQUITOUS PROMOTERS/

The kidney is the major site of expression of the PTH/PTH-related pept ide 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 transc ript-specific in situ hybridization techniques to map the expression o f the PTHR gene and protein and to determine the distribution of P1- a nd PB-driven messenger RNAs in renal tissue. Immunohistochemical and i mmunoelectron microscopic analysis showed that PTHR protein is express ed on both basolateral and luminal membranes of proximal tubular epith elial cells, strongly suggesting a bipolar mode of action of PTH. Rece ptor protein also was detected on the surface of glomerular podocytes. Strikingly, immunoelectron microscopic analysis showed that endotheli al cells of the peritubular vasculature, but not the glomerular vascul ature, contain high levels of PTHR protein. We found that both P1 and P2 are expressed at moderate levels in both cortical and medullary epi thelial cells of nephrons, correlating well with the immunohistochemic al localization of PTHR protein. However, although abundant transcript s were detected in peritubular endothelial cells with P1-specific and coding sequence probes, P2-specific expression was not observed in the se cells. These results provide evidence that the physiological effect s 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 ex pression in vascular endothelial cells, high levels of P1-specific, bu t 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 ti ssues with an abundant vasculature, our results suggest that regulatio n of PTHR gene expression in renal vascular tissue is distinct from th at of other organs.