Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate
Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate
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DOI：
10.1371/journal.pone.0228938
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发表时间：
2020-02-19
期刊：
影响因子：
3.7
通讯作者：
Jahnen-Dechent, Willi
中科院分区：
文献类型：
--
作者：
Babler, Anne;Schmitz, Carlo;Jahnen-Dechent, Willi
钙化可破坏心血管系统和肾脏的器官功能，在慢性肾脏疾病(CKD)患者中尤其常见。根据遗传背景保持的DBA/2胎球蛋白A缺陷小鼠表现出特别严重的软组织钙化，而胎球蛋白A缺陷C57BL/6小鼠保持健康。我们使用分子遗传学分析来确定胎球蛋白-A缺陷小鼠钙化的危险因素。我们试图确定可能受饮食或肠外补充影响的药物治疗靶点。我们研究了胎球蛋白A缺陷的DBA/2和C57BL/6小鼠的杂交后代，以确定与钙化有关的候选危险基因。我们确定Abcc6基因的亚型突变，一种提供全身焦磷酸的肝脏ATP转运体，以及未能调控肾脏中的Trpm6镁转运体与钙化的严重程度有关。易钙化的胎球蛋白-A缺陷小鼠被交替给予胎球蛋白-A饮食镁补充、磷酸盐限制或通过或肠外焦磷酸盐进行治疗。计算机断层扫描、组织学和组织钙测量显示，所有治疗方法均显著减少软组织钙化。我们发现，胎球蛋白-A缺陷的DBA/2小鼠的病理性异位钙化是由三种主要的细胞外和全身钙化抑制物，即胎球蛋白-A、镁和焦磷酸盐的复合缺乏引起的。众所周知，这三种物质都有助于稳定蛋白质-矿物质复合体，从而抑制细胞外液中的矿物质沉淀。我们首次发现了一种复合三重缺乏症，可以通过简单的饮食或肠外补充来治疗。这对晚期CKD患者尤其重要，他们通常表现出血清胎球蛋白-A、镁和焦磷酸水平降低。
Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.