Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Department of Systems Medicine, University of Rome-Tor Vergata, Rome, Italy.
Sci Rep. 2018 Aug 16;8(1):12255. doi: 10.1038/s41598-018-29665-3.
Previous studies suggested that the IGF-1/IGF-1 receptor signaling pathway may contribute to regulate uric acid levels. To confirm this hypothesis, we assessed the effects of the IGF-1-raising genetic variant rs35767 on urate levels in serum and urine, and we investigated IGF-1 ability to modulate the expression of transporters involved in reabsorption and secretion of uric acid in the kidney. The study population included 2794 adult Whites. 24-hour urinary uric acid concentration was available for 229 subjects. rs35767 polymorphism was screened using TaqMan genotyping assays. HEK293 (human embryonic kidney-293) cell line was treated with IGF-1 (1, 5, 10, 50 nM) for 24-hours, and differences in the expression of urate transporters were evaluated via Western Blot and real time rtPCR. Individuals carrying the IGF-1-raising allele (rs35767 T) exhibited significantly lower levels of serum urate according to both additive and recessive models, after correction for gender, age, BMI, glucose tolerance, glomerular filtration rate, and anti-hypertensive treatment. TT genotype carriers displayed higher uricosuria than C allele carriers did, after adjusting for confounders. Exposure of HEK293 cells to IGF-1 resulted in a dose-dependent increase of uric acid transporters deputed to uric acid excretion (MRP4, NPT1 and BCRP), and reduction of GLUT9 expression, the major mediator of uric acid reabsorption, both at mRNA and protein level. We observed a significant association between the functional polymorphism rs35767 near IGF1 with serum urate concentrations and we provide a mechanistic explanation supporting a causal role for IGF-1 in the regulation of uric acid homeostasis.
先前的研究表明，IGF-1/IGF-1 受体信号通路可能有助于调节尿酸水平。为了验证这一假说，我们评估了 IGF-1 升高的遗传变异 rs35767 对血清和尿液中尿酸水平的影响，并研究了 IGF-1 调节肾脏尿酸重吸收和分泌相关转运体表达的能力。研究人群包括 2794 名成年白人。229 名受试者提供了 24 小时尿液尿酸浓度。使用 TaqMan 基因分型检测筛查 rs35767 多态性。用 IGF-1（1、5、10、50 nM）处理 HEK293（人胚肾-293）细胞系 24 小时，通过 Western Blot 和实时 rtPCR 评估尿酸转运体的表达差异。根据加性和隐性模型，携带 IGF-1 升高等位基因（rs35767 T）的个体血清尿酸水平显著降低，校正性别、年龄、BMI、葡萄糖耐量、肾小球滤过率和抗高血压治疗后。调整混杂因素后，TT 基因型携带者的尿酸排泄量高于 C 等位基因携带者。HEK293 细胞暴露于 IGF-1 导致尿酸排泄相关尿酸转运体（MRP4、NPT1 和 BCRP）呈剂量依赖性增加，而 GLUT9 表达减少，后者是尿酸重吸收的主要介质，mRNA 和蛋白水平均减少。我们观察到 IGF1 附近的功能多态性 rs35767 与血清尿酸浓度之间存在显著关联，并且提供了支持 IGF-1 在调节尿酸稳态中起因果作用的机制解释。
