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In Vivo Regulation of Chromogranin A Messenger Ribonucleic Acid in the Parathyroid by 1,25-Dihydroxyvitamin D: Studies in Normal Rats and in Chronic Renal Insufficiency¹

Departments of Medicine and Physiology (E.S., L.C., G.N.H.), McGill University and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada; and NPS Pharmaceuticals (J.F.), Salt Lake City, Utah 84108

Address all correspondence and requests for reprints to: Geoffrey N. Hendy, Ph.D., Calcium Research Laboratory, Room H4.67, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. E-mail: gnhendy{at}medcor.mcgill.ca

Chromogranin-A (CgA) and PTH are the two major secretory products of the parathyroid gland. In vitro, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] increases CgA, but decreases PTH messenger RNA (mRNA) levels. We investigated the physiological significance of the induced changes in CgA expression by examining the effects of 1,25-(OH)₂D₃ on parathyroid CgA mRNA levels in vivo. Normal rats were injected with 1,25-(OH)₂D₃ at 48 and 24 h before blood sampling and isolation of both parathyroid glands. Parathyroid total RNA was extracted and CgA and PTH mRNA quantified by Northern blot analysis. CgA mRNA levels increased 1.6-, 3.2- and 5.6-fold, whereas PTH mRNA levels decreased by 37, 63 and 97%, respectively, with 1,25-(OH)₂D₃ doses of 10, 50, and 250 pmol/100 g BW. Parathyroid gland CgA expression also was examined in rats with mild chronic renal insufficiency, induced by a 5/6 nephrectomy 5 weeks earlier. Chronic renal insufficiency rats, fed normal chow, had elevated serum urea, creatinine, and PTH levels and reduced 1,25-(OH)₂D₃ but normal serum levels of calcium and phosphate. PTH mRNA levels were elevated 4-fold and CgA mRNA levels were 50% lower in the uremic animals. This indicates that the regulation of CgA expression in normocalcemic rats occurs at physiological 1,25-(OH)₂D₃ concentrations. In summary, increases and decreases in serum 1,25-(OH)₂D₃ levels are associated with corresponding increases and decreases in CgA mRNA levels in the parathyroid glands of rats. Therefore, this study is the first to demonstrate the physiological relevance of the earlier in vitro observations.

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