PDF(Pubmed)
Abstract：
Calcineurin inhibitors (CNIs) are widely used in organ transplantation to suppress immunity and prevent allograft rejection. However, some transplant patients receiving CNIs have hypocitraturia, hyperoxaluria and kidney stone with unclear mechanism. We hypothesized that CNIs suppress activities of urinary calcineurin, which may serve as the stone inhibitor. This study aimed to investigate effects of calcineurin B (CNB) on calcium oxalate monohydrate (COM) stone formation. Sequence and structural analyses revealed that CNB contained four EF-hand (Ca2+-binding) domains, which are known to regulate Ca2+ homeostasis and likely to affect COM crystals. Various crystal assays revealed that CNB dramatically inhibited COM crystallization, crystal growth and crystal aggregation. At an equal amount, degrees of its inhibition against crystallization and crystal growth were slightly inferior to total urinary proteins (TUPs) from healthy subjects that are known to strongly inhibit COM stone formation. Surprisingly, its inhibitory effect against crystal aggregation was slightly superior to TUPs. While TUPs dramatically inhibited crystal-cell adhesion, CNB had no effect on this process. Ca2+-affinity assay revealed that CNB strongly bound Ca2+ at a comparable degree as of TUPs. These findings indicate that CNB serves as a novel inhibitor of COM crystallization, growth and aggregation via its high Ca2+-affinity property.
摘要：
钙调神经磷酸酶抑制剂(CNIs)广泛用于器官移植,以抑制免疫和预防同种异体移植排斥反应。然而,一些接受CNIs的移植患者有低血尿，高草酸尿症和肾结石，机制不明确。我们假设CNIs抑制尿钙调磷酸酶的活性，可以作为结石抑制剂。本研究旨在探讨钙调神经磷酸酶B(CNB)对草酸钙一水合物(COM)结石形成的影响。序列和结构分析显示，CNB含有四个EF-手（Ca2+结合）结构域，已知可调节Ca2稳态并可能影响COM晶体。各种晶体试验表明，CNB显著抑制COM结晶，晶体生长和晶体聚集。等量,其对结晶和晶体生长的抑制程度略低于已知强烈抑制COM结石形成的健康受试者的总尿蛋白（TUP）。令人惊讶的是,其对晶体聚集的抑制作用略优于TUPs。虽然TUP显著抑制晶体细胞粘附，CNB对该过程没有影响。Ca2亲和力测定显示，CNB与Ca2结合的程度与TUP相当。这些发现表明CNB是一种新型的COM结晶抑制剂，通过其高Ca2+亲和力生长和聚集。
