Rowe Peter S N, Zelenchuk Lesya V, Laurence Jennifer S, Lee Phil, Brooks William M, McCarthy Ellen T
The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
Pharmaceutical Chemistry, University of Kansas, Kansas City, Lawrence, Kansas;
Am J Physiol Renal Physiol. 2015 Nov 1;309(9):F764-9. doi: 10.1152/ajprenal.00201.2015. Epub 2015 Sep 2.
Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+)-based contrast agents (GBCAs) in patients with kidney disease. The release of toxic Gd3+ from GBCAs likely plays a major role in NSF pathophysiology. The cause and etiology of Gd3+ release from GBCAs is unknown. Increased Acidic Serine Aspartate Rich MEPE-associated peptides (ASARM peptides) induce bone mineralization abnormalities and contribute to renal phosphate-handling defects in inherited hypophosphatemic rickets and tumor-induced osteomalacia. The proteolytic cleavage of related bone matrix proteins with ASARM motifs results in release of ASARM peptide into bone and circulation. ASARM peptides are acidic, reactive, phosphorylated inhibitors of mineralization that bind Ca2+ and hydroxyapatite. Since the ionic radius of Gd3+ is close to that of Ca2+, we hypothesized that ASARM peptides increase the risk of NSF by inducing release of Gd3+ from GBCAs. Here, we show 1) ASARM peptides bind and induce release of Gd3+ from GBCAs in vitro and in vivo; 2) A bioengineered peptide (SPR4) stabilizes the Gd3+-GBCA complex by specifically binding to ASARM peptide in vitro and in vivo; and 3) SPR4 peptide infusion prevents GBCA-induced NSF-like pathology in a murine model with increased ASARM peptide (Hyp mouse). We conclude ASARM peptides may play a role in NSF and SPR4 peptide is a candidate adjuvant for preventing or reducing risk of disease.
肾源性系统性纤维化（NSF）是一种与肾病患者使用钆（Gd3+）基造影剂（GBCAs）相关的严重病症。GBCAs中有毒Gd3+的释放可能在NSF病理生理过程中起主要作用。GBCAs释放Gd3+的原因和机制尚不清楚。富含酸性丝氨酸天冬氨酸的MEPE相关肽（ASARM肽）增加会导致骨矿化异常，并在遗传性低磷性佝偻病和肿瘤诱导的骨软化症中导致肾脏磷酸盐处理缺陷。具有ASARM基序的相关骨基质蛋白的蛋白水解切割导致ASARM肽释放到骨骼和循环中。ASARM肽是酸性、有反应性、磷酸化的矿化抑制剂，可结合Ca2+和羟基磷灰石。由于Gd3+的离子半径与Ca2+相近，我们推测ASARM肽通过诱导GBCAs释放Gd3+增加了NSF的风险。在此，我们表明：1）ASARM肽在体外和体内均可结合并诱导GBCAs释放Gd3+；2）一种生物工程肽（SPR4）通过在体外和体内特异性结合ASARM肽来稳定Gd3+-GBCA复合物；3）在ASARM肽增加的小鼠模型（Hyp小鼠）中，输注SPR4肽可预防GBCA诱导的类似NSF的病理变化。我们得出结论，ASARM肽可能在NSF中起作用，而SPR4肽是预防或降低疾病风险的候选佐剂。
