RT Journal Article
SR Electronic
T1 Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 624650
DO 10.1101/624650
A1 Sébastien Bender
A1 Maria Victoria Ayala
A1 Amélie Bonaud
A1 Vincent Javaugue
A1 Claire Carrion
A1 Christelle Oblet
A1 Alexia Rinsant
A1 Nathalie Quellard
A1 Sihem Kaaki
A1 Zeliha Oruc
A1 François Boyer
A1 Agnès Paquet
A1 Nicolas Pons
A1 Bastien Hervé
A1 Mohamad Omar Ashi
A1 Arnaud Jaccard
A1 Laurent Delpy
A1 Guy Touchard
A1 Michel Cogné
A1 Frank Bridoux
A1 Christophe Sirac
YR 2019
UL http://biorxiv.org/content/early/2019/05/02/624650.abstract
AB Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.