Vitamin D receptor agonists as anti-inflammatory agents

Background: secondary hyperparathyroidism (SHPT) is an early complication of chronic kidney disease (CKD). Maintaining the level of 25(OH)D and parathyroid hormone concentrations in the target range reduce its associated complications (fractures and cardiovascular calcification). Aims: to examine the effectiveness of vitamin D supplementation and selective vitamin D receptor agonists treatment on SHPT in CKD. Material and methods: prospective observational study to evaluate the efficacy and safety of vitamin D therapy SHPT in 54 in patients with CKD. The first phase (24 weeks) – treatment of suboptimal 25-hydroxycalciferol (25(OH)D) levels. The second (16 weeks) – treatment colecalciferol-resistant SHPT by combination of cholecalciferol with paricalcitol. Blood samples were taken to assess parathyroid hormone (PTH), 25(OH)D, creatinine, calcium, phosphorus levels and calcium excretion. Results: After 8 weeks of cholecalciferol treatment all patients achieved 25(OH)D levels above 20 ng/ml, however 78% of patients still had SHPT. After 16 weeks, the decrease of PTH was achieved in all patients, but significantly only in patients with CKD 2 (19.2%, p< 0.01) and 3 (31%, p <0.05), compared with CKD 4 (17%, p >0.05). After 24 weeks of therapy, PTH normalized in all patients with CKD 2, in 15 (79%) with CKD 3 and in 9 (50%) patients with CKD 4. Cholecalciferol treatment resulted in a substantial increase in 25(OH)D levels with minimal or no impact on calcium, phosphorus levels and kidney function. After 24 weeks we initiated combination therapy (cholecalciferol and paricalcitol) for patients with colecalciferol-resistant SHPT (n=13). PTH levels decreased from 149.1±13.4 to 118.2±14.1 pg/ml at 8 weeks, and to 93.1±9.7 pg/ml (p <0.05) at 16 weeks of treatment. No significant differences in serum calcium, phosphorus or urinary calcium levels. Normalization of PTH was achieved in all patients with CKD 3 and in 8 patients with stage 4. One patient with CKD 4 needed an increase in paricalcitol dose. Conclusion: Cholecalciferol can be used in correcting vitamin D deficiency in patients with all stages of CKD, however, its effectiveness in reducing PTH in stage 4 is limited. Selective analogs, such as paricalcitol, were well-tolerated and effectively decreased PTH levels.

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Different vitamin D receptor agonists exhibit differential effects on endothelial function and aortic gene expression in 5/6 nephrectomized rats

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2014.12.002 ◽

2015 ◽

Vol 148 ◽

pp. 202-209 ◽

Cited By ~ 20

Author(s):

J. Ruth Wu-Wong ◽

Xinmin Li ◽

Yung-wu Chen

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Endothelial Function ◽

Vitamin D Receptor ◽

Differential Effects ◽

Receptor Agonists

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Vitamin D Receptor Agonists Upregulate Klotho and Decrease Vascular Calcification in Mice With Mild Chronic Kidney Disease

American Journal of Kidney Diseases ◽

10.1053/j.ajkd.2012.02.149 ◽

2012 ◽

Vol 59 (4) ◽

pp. B50

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Kidney Disease ◽

Vascular Calcification ◽

Vitamin D Receptor ◽

Receptor Agonists

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TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.2019111206 ◽

2020 ◽

Vol 31 (9) ◽

pp. 2026-2042 ◽

Cited By ~ 1

Author(s):

Sandra Rayego-Mateos ◽

Jose Luis Morgado-Pascual ◽

José Manuel Valdivielso ◽

Ana Belén Sanz ◽

Enrique Bosch-Panadero ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Cultured Cells ◽

Kidney Injury ◽

Preclinical Model ◽

Protein Levels ◽

Inflammatory State ◽

Anti Inflammatory ◽

Injury Models ◽

Inflammatory Effect

BackgroundCKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.MethodsModulation of the noncanonical NF-κB2 pathway and its component TNF receptor–associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.ResultsIn PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA’s effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2–dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.ConclusionsThese data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA’s effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

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