Huang Z Q, Sanders P W
Nephrology Research and Training Center, Division of Nephrology, Birmingham, Alabama, USA.
Lab Invest. 1995 Dec;73(6):810-7.
Cast nephropathy in multiple myeloma patients is caused by heterotypic aggregation of Tamm-Horsfall glycoprotein (THP) with monoclonal light chains (Bence Jones protein, BJP). Co-aggregation of these proteins is triggered by the binding of BJP to a specific peptide portion of THP. Defining those factors that alter the interaction between BJP and THP may help to understand further the pathogenesis of cast nephropathy and serve to decrease the morbidity and mortality of cast nephropathy. We hypothesized that pH, calcium, furosemide, and the carbohydrate moiety of THP all modulate the protein-protein interaction between BJP and THP.
Binding affinity and aggregation rate of human THP with two human nephrotoxic BJP were tested at pH 8.5, 7.4, and 5.0. The effects of calcium, furosemide, and free sialic acid were also evaluated. Binding and aggregation of BJP with THP purified from normal volunteers treated with oral colchicine were observed. The carbohydrate components of THP were also analyzed.
An acidic environment increased initial binding rate and produced a parallel increase in the aggregation rate of THP with BJP. Calcium and furosemide enhanced aggregation rates without interfering with binding. Colchicine treatment decreased the amount of sialic acid linked alpha(2-6) to galactose (NeuAc alpha 2-6Gal) and sialic acid linked alpha(2-3) to galactose (NeuAc alpha 2-3Gal) on THP and thereby decreased the aggregation rate with BJP without altering binding. Addition of free sialic acid did not alter binding but did decrease aggregation rates of the two proteins.
Environmental conditions modulate BJP-THP interactions and may be responsible for inducing case nephropathy in multiple myeloma. Modification of carbohydrate components of THP or use of oligosaccharides may decrease or prevent cast nephropathy.
多发性骨髓瘤患者的管型肾病是由Tamm-Horsfall糖蛋白（THP）与单克隆轻链（本周氏蛋白，BJP）的异型聚集引起的。这些蛋白质的共聚集是由BJP与THP的特定肽段结合引发的。确定那些改变BJP与THP相互作用的因素可能有助于进一步理解管型肾病的发病机制，并有助于降低管型肾病的发病率和死亡率。我们假设pH值、钙、呋塞米和THP的碳水化合物部分均调节BJP与THP之间的蛋白质-蛋白质相互作用。
在pH值为8.5、7.4和5.0的条件下，测试了人THP与两种人肾毒性BJP的结合亲和力和聚集速率。还评估了钙、呋塞米和游离唾液酸的作用。观察了BJP与从口服秋水仙碱治疗的正常志愿者中纯化的THP的结合和聚集情况。还分析了THP的碳水化合物成分。
酸性环境提高了初始结合速率，并使THP与BJP的聚集速率平行增加。钙和呋塞米提高了聚集速率，而不干扰结合。秋水仙碱治疗减少了THP上与半乳糖以α(2-6)连接的唾液酸（NeuAcα2-6Gal）和与半乳糖以α(2-3)连接的唾液酸（NeuAcα2-3Gal）的量，从而降低了与BJP的聚集速率，而不改变结合。添加游离唾液酸不改变结合，但确实降低了两种蛋白质的聚集速率。
环境条件调节BJP-THP相互作用，可能是多发性骨髓瘤中诱导管型肾病发展的原因。THP碳水化合物成分的修饰或使用寡糖可能减少或预防管型肾病。
