TY - JOUR
T1 - A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content
AU - Takahashi, Fumiaki
AU - Finch, Jane L.
AU - Denda, Masashi
AU - Dusso, Adriana S.
AU - Brown, Alex J.
AU - Slatopolsky, Eduardo
N1 - Funding Information:
From the Renal Division, cine, Washington University MO. Received October 19, 1996; accepted in revisedfotm ruary 21, 1997. Supported in part by National Institute of Diabetes, Digestive, and Kidney Diseases grants no. DK-09976, DK-30178, and DK-07126, and by a grantfrom Abbott Pharmaceuticals, Abbott Park, IL. Address reprint requests to Eduardo Slatopolsky, MD, Department of Internal Medicine, Renal Division, Washington University School of Medicine, Ckromalloy American Kidney Center, 660 South Euclid Ave, Bon 8129, St Louis, MO 63110-1093. 0 1997 by the National Kidney Foundation, 0272-6386/97/3001-0015$3.00/O
PY - 1997/7
Y1 - 1997/7
N2 - We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19- nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 ± 10.2 pg/mL in the uremic control group to 25.7 ± 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 ± 0.05 to 4.85 ± 0.06 mg/dL; P < 0.05) and phosphorus (4.34 ± 0.30 to 6.67 ± 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor- 1,25-(OH)2D2 decreased PTH to 20.7 ± 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25- (OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rate (25 ng:30.4 ± 2.0, P < 0.05, and 100 ng:27.9 ± 3.2, P < 0.01, v 48.4 ± 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 ± 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 ± 11.9, P < 0.05, and 100 ng:78.4 ± 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D3 because intestinal VDR correlated directly with serum 1,28-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.
AB - We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19- nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 ± 10.2 pg/mL in the uremic control group to 25.7 ± 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 ± 0.05 to 4.85 ± 0.06 mg/dL; P < 0.05) and phosphorus (4.34 ± 0.30 to 6.67 ± 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor- 1,25-(OH)2D2 decreased PTH to 20.7 ± 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25- (OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rate (25 ng:30.4 ± 2.0, P < 0.05, and 100 ng:27.9 ± 3.2, P < 0.01, v 48.4 ± 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 ± 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 ± 11.9, P < 0.05, and 100 ng:78.4 ± 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D3 because intestinal VDR correlated directly with serum 1,28-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.
KW - Calcitriol
KW - Parathyroid hormone
KW - Uremia
KW - Vitamin D analogs
UR - http://www.scopus.com/inward/record.url?scp=0030837556&partnerID=8YFLogxK
U2 - 10.1016/S0272-6386(97)90571-0
DO - 10.1016/S0272-6386(97)90571-0
M3 - Article
C2 - 9214408
AN - SCOPUS:0030837556
SN - 0272-6386
VL - 30
SP - 105
EP - 112
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 1
ER -