Do ASARM peptides play a role in nephrogenic systemic fibrosis?
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.
The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; prowe@kumc.edu.
Peter S N
PS
Rowe
The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
Lesya V
LV
Zelenchuk
Pharmaceutical Chemistry, University of Kansas, Kansas City, Lawrence, Kansas;
Jennifer S
JS
Laurence
Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, Kansas; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas; and.
Phil
P
Lee
Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, Kansas; Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.
William M
WM
Brooks
The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
Ellen T
ET
McCarthy
D000818:Animals; D003287:Contrast Media; D019610:Cytoprotection; D004195:Disease Models, Animal; D004355:Drug Stability; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D053098:Familial Hypophosphatemic Rickets / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D019786:Gadolinium DTPA; D006023:Glycoproteins / Q000378:metabolism*; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives*; D008810:Mice, Inbred C57BL; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009942:Organometallic Compounds; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D055114:X-Ray Microtomography
D003287:Contrast Media; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; C518716:Mepe protein, mouse; D009942:Organometallic Compounds; D010446:Peptide Fragments; D010750:Phosphoproteins; C064572:gadobenic acid; D008536:Meglumine; D000089703:Fibroblast Growth Factor-23; C064925:gadodiamide; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D019786:Gadolinium DTPA
DMP1; FGF23; MEPE; PHEX; chronic kidney disease; nephrogenic system fibrosis; osteopontin; sclerostin