Background
Paricalcitol is the third generation of vitamin D analog, and is a selective activator of VDR used for the treatment of secondary hyperparathyroidism. The vascular calcification process in chronic kidney disease is also directly influenced by paricalcitol. [1]
Vitamin D has important roles in physiological processes, and is primarily involved in calcium and phosphorus homeostasis and bone metabolism. Vitamin D can prevent or ameliorate inflammatory disease in animal autoimmune disease models and in patients. The mechanism by which vitamin D regulates inflammatory response appears to be dependent on the activation of regulatory CD4+T cells. [2]
The intraperitoneal administration of paricalcitol modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. The treatment reduced peritoneal IL-17 levels. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice. In a rat model of gentamicin-induced renal injury, paricalcitol preventes upregulated inflammatory cytokines, nuclear factor-kappaB and phosphorylated ERK1/2 expression, and adhesion molecules (monocyte chemoat?tractant protein-1, ICAM-1, VCAM-1), and they reversed the transforming growth factor (TGF)-beta1-induced epithelial-to-mesenchymal transition process and extracel?lular matrix accumulation. [2]
Paricalcitol has a good effect on proteinuria in non-dialysis CKD patients with secondary hyperparathyroidism treated according to Kidney Disease. After treatment with paricalcitol, statistically significant reduction (paired t-test) in 24hUA (P < 0.011) and 24hUQP (P < 0.0001) are found. The reduction of UACR was not significant (P = 0.074). In the observational period no statistically significant reduction in 24hABP was found. Treatment with 1 mg paricalcitol daily according to clinical practice in non-dialysisCKDpatients with secondary hyperparathyroidism and proteinuria significantly reduces 24hUA and 24hUQP without significant change in 24hABP. [3]
参考文献:
[1]Darko Duplancic, Marijan Cesarik, Nikola Kolja Poljak et al. The influence of selective vitamin D receptor activator paricalcitol on cardiovascular system and cardiorenal protection.? Clinical Interventions in Aging 2013:8 149–156
[2]Guadalupe T. Gonza′lez-Mateo et al. Paricalcitol Reduces Peritoneal Fibrosis in Mice through the Activation of Regulatory T Cells and Reduction in IL-17 Production. PLOS ONE October 2014 | Volume 9 | Issue 10 | e108477
[3]Nina Hojs, Sebastjan Bevc et al. Paricalcitol Reduces Proteinuria in Non-Dialysis Chronic Kidney Disease Patients Therapeutic Apheresis and Dialysis 2013; 17(4):368–372
Protocol
Animal experiment: | After TAC or sham surgery, a subset of the mice is treated with paricalcitol, a selective vitamin D receptor activator, which activates the VDR, at a final dose of 300 ng/kg/day. Paricalcitol is dissolved in a 95% propylene glycol and 5% ethyl alcohol solution. Mice are intraperitoneally injected with paricalcitol (or vehicle only) three times per week on Monday, Wednesday and Friday for five consecutive weeks. An established anti-hypertrophic and anti-fibrotic treatment, namely the angiotensin II receptor blocker (ARB) losartan is also included. Previous experiments have shown it is feasible and efficacious to dissolve losartan in the drinking water at a concentration of 30 mg/kg/day; mice are treated for five consecutive weeks. So, in total eight groups are studied. Sham (n=10), TAC (n=10), Sham + losartan (Sham-los, n=10), TAC + losartan (TAC-los, n=10), Sham + paricalcitol (Sham-pari, n=10), TAC + paricalcitol (TAC-pari, n=10), Sham + paricalcitol + losartan (Sham-combi, n=10) and TAC + paricalcitol + losartan (TAC-combi, n=10). |
参考文献: [1]. Martinez-Moreno JM, et al. In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/beta-catenin activation. Am J Physiol Renal Physiol. 2012 Aug 8.
[2]. Meems LM, et al. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload. J Steroid Biochem Mol Biol. 2012 Jul 16;132(3-5):282-289. |
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