title: Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model.
abstract: A common renal complication of multiple myeloma is "myeloma kidney," a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma.
authors.affiliation: Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Ying
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Allen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Curtis
authors.forename: Kristal J
authors.initials: KJ
authors.lastname: Aaron
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sanders
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D017207:Rats, Sprague-Dawley; D058949:Uromodulin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D022801:Complementarity Determining Regions; D007147:Immunoglobulin Light Chains; D010456:Peptides, Cyclic; C548614:Umod protein, rat; D058949:Uromodulin