Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies
Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies
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DOI：
10.1093/ajh/hpy154
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发表时间：
2019-01-01
影响因子：
3.2
通讯作者：
Freundlich, Michael
中科院分区：
文献类型：
--
作者：
Czaya, Brian;Seeherunvong, Wacharee;Freundlich, Michael
背景：在尿毒症动物中，维生素D受体（VDR）激动剂如帕尔卡尔醇（Pc）可减轻心脏肥厚，但这种效果在慢性肾病患者中尚未得到一致的复制。成纤维细胞生长因子23 （FGF23）水平升高通过激活心肌钙调磷酸酶/活化T细胞核因子（NFAT）轴引起心肌肥厚，并可能拮抗VDR激动剂治疗的心脏保护作用。我们假设Pc的有效性可能取决于当前循环中FGF23的水平，并且可以通过联合使用泛FGF23受体（FGFR）阻滞剂（PD173074）来增强。方法用Pc或PD173074或两者同时治疗5/6肾切除术大鼠，检测心肌肾素-血管紧张素系统、VDR、FGFR4和钙调磷酸酶/NFAT靶基因mRNA表达。在接受血液透析的青少年中，我们分析了连续超声心动图、血压和连续FGF23测量值，以及它们与肠外Pc累积给药剂量的关系。结果在尿毒症大鼠和血液透析患者中，血浆中FGF23的剂量/浓度与心脏质量呈负相关（P < 0.005），与高血压无关。尽管持续升高的FGF23水平和心肌FGFR4激活，Pc抑制上调的心肌钙调神经磷酸酶/NFAT靶基因，并且通过共同给药PD173074，效果被放大。结论Pc对尿毒症心肌肥厚的有益作用与FGF23水平升高相抵消。阻断fgf23介导的信号通路增加了pc诱导的心肌钙调磷酸酶/NFAT系统的抑制。在尿毒症心肌病患者的治疗中应考虑高剂量的Pc。
BACKGROUNDIn uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074).METHODSIn rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc.RESULTSThe ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074.CONCLUSIONSThe beneficial effects of Pc on uremic cardiac hypertrophy are counter-balanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.