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Evidence for Protein Kinase C Involvement in the Regulation of Renal 25-Hydroxyvitamin D₃-24-Hydroxylase^*

SUZAN MANDLA, AVIHU BONEH and HARRIET S. TENENHOUSE

Medical Research Council Genetics Group, Department of Pediatrics and Centre for Human Genetics, Department of Biology, McGill University, McGill University-Montreal Children's Hospital Research Institute Montreal, Quebec H3H1P3 Canada

Address requests for reprints to: Dr. H. S. Tenenhouse, Medical Research Council Genetics Group, Montreal Children’s Hospital, 2300 Tupper Street, Montreal, Quebec H3H 1P3 Canada.

Abstract

Although calcium-activated, phospholipid-dependent protein kinase (protein kinase C) has been implicated in the regulation of various steroidogenic pathways, comparatively little is known of its role in the metabolism of vitamin D. The present study was undertaken to determine whether protein kinase C is involved in the regulation of renal mitochondrial 25- hydroxyvitamin D3-24-hydroxylase (24-hydroxylase), the first enzyme in the C-24 oxidation pathway, a major catabolic pathway for vitamin D metabolites in kidney and other target tissues. We examined the effect of phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C, on 24-hydroxylase activity in fresh mouse renal tubules and correlated the changes in 24,25-dihydroxyvitamin D₃ [24,25-(OH)₂D₃] production with translocation of protein kinase C and phosphorylation of mitochondrial proteins. PMA stimulated 24,25-(OH)₂D₃ synthesis, protein kinase C translocation from the cytosolic to the mitochondrial fraction, and phosphorylation of 30-35 K, 40 K, and 50 K mitochondrial proteins derived from ³²P-labeled tubules. 4-Phorbol 12,13 didecanoate, an inert analog of PMA, did not elicit any of these effects. The synthetic diacylglycerol, oleoylacetyl glycerol, also stimulated 24,25-(OH)₂D₃ synthesis, whereas the protein kinase C inhibitors, H-7 and staurosporine, inhibited 24-hydroxylase activity. PMA did not further stimulate 24,25- (OH)₂D₃ production in tubules derived from mutant (Hyp) mice in which 24-hydroxylase and protein kinase C activities are elevated relative to normal. However, after treatment with H-7, 24-hydroxylase activity was reduced in both strains, and genotype differences were no longer apparent. Finally, H-7 failed to inhibit the induced renal 24-hydroxylase in tubules isolated from 1,25-dihydroxyvitamin D₃-treated mice. These findings suggest a role for protein kinase C in the regulation of constitutive renal 24-hydroxylase and implicate the kinase in the aberrant expression of the hydroxylase in the Hyp mouse. (Endocrinology 127: 2639–2647, 1990)

Footnotes

^* This work was supported by grants from the Kidney Foundation of Canada and the Medical Research Council of Canada. This is publication No. 90-027 from the McGill University-Montreal Children’s Hospital Research Institute.

Recipient of a Fonds pour la formation de chercheurs et l'aide a la recherche Studentship.

Recipient of a McGill University-Montreal Children's Hospital Research Institute Fellowship and a McGill University Postgraduate Studentship Award.

Received April 3, 1990.

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