Differential Inhibition of Renin mRNA Expression by Paricalcitol and Calcitriol in C57/BL6 Mice

Abstract

Background/Aims: 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 iCa²⁺ in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 µg/kg s.c.) 3 days/week for 9 days. Results: Paricalcitol produced PTH suppression from 0.03 to 1.0 µg/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 µg/kg (0.037 ± 0.002, 0.027 ± 0.003; vehicle = 0.054 ± 0.003) but produced no increases iCa²⁺ 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 µg/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 iCa²⁺ (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 iCa²⁺ were observed at doses only 3-fold above those necessary to elicit renin suppression.

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

“…To test this concept, in the current study we treated a mouse model of diabetic nephropathy with a combination of losartan and paricalcitol. Paricalcitol (19-nor-1,25-dihydroxyvitamin D 2 ) is an activated vitamin D analog and activates VDR with a high affinity, and we used paricalcitol because it suppresses renin expression in mice with the same potency as calcitriol but without induction of hypercalcemia (31). Our data demonstrated that the combination of an ARB and a vitamin D analog markedly ameliorated renal injury because of more effective inhibition of the RAS within the kidney.…”

Vitamin D Receptor Activation Protects Against Myocardial Reperfusion Injury Through Inhibition of Apoptosis and Modulation of Autophagy

“…The vehicle group received vehicle injections using the same schedule. The pharmacological dosages were chosen based on previous reports (4,6,15). The surgical procedures were performed as described in previous studies (16,52).…”

Paricalcitol may improve oxidative DNA damage on experimental amikacin-induced nephrotoxicity model

“…[5][6][7] Recently, it has been shown that paricalcitol has anti-oxidant effects on renal tissue and suppresses the reninangiotensin system (RAS) in diabetic kidney. 8,9 Fryer et al 10 demonstrated that paricalcitol suppresses renal renin expression. It has also been recently reported that the combination of paricalcitol and enalapril treatment ameliorates oxidative injury by suppressing reactive oxygen species generating enzyme NADPH oxidase activity and by up regulating the antioxidant defense system in a uremic rat model of atherosclerosis.…”