Doxercalciferol (0.083, 0.167 or 0.333 μg/kg, i.p.) elevates serum phosphorus at Week 6 in 5/6 nephrectomized (NX) rats. Doxercalciferol (0.167 and 0.333 μg/kg) also increases serum calcium and Ca × P at Weeks 2 and 6, and enhances increased pulse wave velocity (PWV) at Week 6 in 5/6 nephrectomized (NX) rats. Doxercalciferol blocks PTH from rising at 0.083 μg/kg, and lowers serum PTH to the SHAM level[1]. Doxercalciferol (125 ng/kg, i.p. thrice per week) increases expression of VDR mRNA level and renal expression of TRPV5 in NON mice fed a HF diet. Doxercalciferol also improves proteinuria, prevents loss of podocytes, and accumulation of extracellular matrix proteins in HF diet-induced mice. Doxercalciferol inhibits the expression of profibrotic growth factors (TGF-β, PAI-1, and connective tissue growth factor (CTGF)), and blocks increased expression of the renin-angiotensin-aldosterone system in mice fed a HF diet. Furthermore, Doxercalciferol suppresses macrophage infiltration, decreases NF-κb activity, and preventes expression of proinflammatory cytokine and the increase in renal lipid accumulation in mice fed a HF diet[2]. Doxercalciferol (30 ng/kg, i.p. thrice per week) prevents albuminuria, markedly attenuates podocyte loss and apoptosis, and reduces glomerular fibrosis in streptozotocin-induced diabetic mice[3].
In Vitro
Kinase Assay
Cell Assay
Animal Administration
Rats[1] Male, Sprague-Dawley, 5/6 nephrectomized (NX) rats (∼200 gm) are used 1 week after nephrectomy. The nephrectomy is performed using a standard two-step surgical ablation procedure. Beginning 2 weeks post-nephrectomy, rats are maintained on a high phosphorus diet (0.9% phosphorus and 0.6% calcium) for the duration of the study to induce secondary hyperparathyroidism. On Day 0, SHAM and 5/6 NX rats (n = 7-10 per group) receive vehicle (5% EtOH/95% propylene glycol; 0.4 mL/kg; i.p.) or VDRA (paricalcitol or Doxercalciferol; 0.083, 0.167 or 0.333 μg/kg; intraperitoneally) three times per week for 41 days (n = 6-10 per group). These doses are chosen based on the fact that lower doses (0.021 and 0.042 μg/kg; i.p.) of either compound are not PTH suppressive after 2 or 6 weeks of treatment in this model of CKD. On Days 0, 13 and 41, blood is collected (24 h post-dose). On Days 0, 13 and 41 (24 h post-dose), animals are anaesthetized with ketamine (50 mg/kg) and blood is collected via the tail vein for PTH and serum blood chemistry determinations[1].
References
[1]. Noonan W, et al. Differential effects of vitamin D receptor activators on aortic calcification and pulse wave velocity in uraemic rats. Nephrol Dial Transplant. 2008 Dec;23(12):3824-30.
[2]. Wang XX, et al. Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am J Physiol Renal Physiol. 2011 Mar;300(3):F801-10.
[3]. Wang Y, et al. Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol. 2012 Dec;23(12):1977-86.
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