Differential inhibition of renin mRNA expression by paricalcitol and calcitriol in C57/BL6 mice.
OBJECTIVE
Vitamin D receptor activators (VDRAs) may suppress renin expression and VDR-mediated renin inhibitors may offer a novel mechanism to control the RAS.


METHODS
We delineated the effects of paricalcitol and calcitriol on PTH, renin, and iCa(2+) in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 microg/kg s.c.) 3 days/week for 9 days.


RESULTS
Paricalcitol produced PTH suppression from 0.03 to 1.0 microg/kg (values between 9.7 +/- 3.3 and 20.7 +/- 4.7 pg/ml; vehicle = 88.0 +/- 16.9) and elicited dose-dependent reductions in renin/GAPDH expression at 0.33 and 1.0 microg/kg (0.037 +/- 0.002, 0.027 +/- 0.003; vehicle = 0.054 +/- 0.003) but produced no increases iCa(2+) at any dose tested. Calcitrol produced PTH suppression at all doses tested (between 6.4 +/- 1.2 and 29.5 +/- 17.2 pg/ml) and renin suppression at 0.10, 0.33, and 1.0 microg/kg (0.029 +/- 0.002, 0.031 +/- 0.003, and 0.038 +/- 0.02). However, at 0.33 and 1.0 mg/kg, calcitriol produced increases iCa(2+) (1.31 +/- 0.03 and 1.48 +/- 0.02 mmol/l; vehicle = 1.23 +/- 0.02 mmol/l).


CONCLUSIONS
Paricalcitol produces significant, dose-dependent suppression of renin expression in the absence of hypercalcemia at doses 10-fold above those necessary for PTH suppression. Calcitriol also produced suppression of renin at doses at least 10-fold above those required for PTH suppression, but increases in iCa(2+) were observed at doses only 3-fold above those necessary to elicit renin suppression.
Fryer
Ryan M
RM
Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA. ryan.fryer@abbott.com
Rakestraw
Pamela A
PA
Nakane
Masaki
M
Dixon
Doug
D
Banfor
Patricia N
PN
Koch
Kristin A
KA
Wu-Wong
J Ruth
JR
Reinhart
Glenn A
GA
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004872:Ergocalciferols / Q000008:administration & dosage*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D004872:Ergocalciferols; D010281:Parathyroid Hormone; C084656:paricalcitol; D012083:Renin; D002117:Calcitriol; D002118:Calcium