Kumar Vivek, Farell Gerard, Yu Shihui, Harrington Sean, Fitzpatrick Lorraine, Rzewuska Ewa, Miller Virginia M, Lieske John C
Division of Nephrology, Mayo Clinic College of Medicine, Rochester, MN, USA.
J Investig Med. 2006 Nov;54(7):412-24. doi: 10.2310/6650.2006.06021.
The earliest lesion in the kidneys of idiopathic calcium oxalate stone formers is deposition of calcium phosphate in the interstitium, termed a Randall's plaque. Yet the cellular and molecular factors leading to their formation are unknown.
The influence of urinary proteins on adhesion of preformed calcium oxalate crystals to rat continuous inner medullary collecting duct (cIMCD) cells was studied in vitro, and cIMCD cells were also exposed to calcifying media containing beta-glycerophosphate for up to 28 days. Renal tissue was obtained from a stone-forming and non-stone-forming individual at the time of nephrectomy. These nanoparticles, isolated from renal stones obtained at the time of surgical resection, were analyzed and propagated in standard cell culture medium.
Urinary proteins influence crystal adhesion to renal epithelial cells, and this activity is abnormal in the urine of stone-forming patients. cIMCD cells assumed an osteoblastic phenotype when exposed to the calcifying medium, expressing two bone matrix proteins (osteopontin and bone sialoprotein) that were also identified in the kidney of the stone-forming patient and associated with crystal deposition. Nanoparticles were propagated from the majority of renal stones. Isolates were susceptible to selected metabolic inhibitors and antibiotics and contained conserved bacterial proteins and deoxyribonucleic acid (DNA).
These results suggest new paradigms for Randall's plaque formation and idiopathic calcium oxalate stone disease. It seems unlikely that these events are driven solely by physical chemistry; rather, they are critically influenced by specific proteins and cellular responses, and understanding these events will provide clues toward novel therapeutic targets.
特发性草酸钙结石患者肾脏最早的病变是间质中磷酸钙沉积，即所谓的兰德尔斑。然而，导致其形成的细胞和分子因素尚不清楚。
在体外研究了尿蛋白对预先形成的草酸钙晶体与大鼠连续髓质内集合管（cIMCD）细胞黏附的影响，并且将cIMCD细胞暴露于含β-甘油磷酸的钙化培养基中长达28天。在肾切除时从结石形成者和非结石形成者获取肾组织。对这些从手术切除时获得的肾结石中分离出的纳米颗粒进行分析，并在标准细胞培养基中进行培养。
尿蛋白影响晶体与肾上皮细胞的黏附，并且这种活性在结石形成患者的尿液中异常。当暴露于钙化培养基时，cIMCD细胞呈现成骨细胞表型，表达两种骨基质蛋白（骨桥蛋白和骨唾液蛋白），这两种蛋白也在结石形成患者的肾脏中被鉴定出，并与晶体沉积有关。纳米颗粒从大多数肾结石中培养出来。分离物对选定的代谢抑制剂和抗生素敏感，并含有保守的细菌蛋白和脱氧核糖核酸（DNA）。
这些结果为兰德尔斑的形成和特发性草酸钙结石病提出了新的范例。这些事件似乎不太可能仅由物理化学驱动；相反，它们受到特定蛋白质和细胞反应的严重影响，了解这些事件将为新的治疗靶点提供线索。
