Naslov
A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome

Autori
Odiatis, Christoforos ; Savva, Isavella ; Pieri , Myrtani ; Ioannou, Pavlos ; Petrou, Petros ; Papagregoriou, Gregory ; Antoniadou, Kyriaki ; Makrides, Neoklis ; Stefanou, Charalambos ; Galešić Ljubanović, Danica ; Nikolaou, Georgios ; Borza, Dorin-Bogdan ; Stylianou, Kostas ; Gross, Oliver ; Deltas, Constantinos

Izvornik
Matrix biology plus (2590-0285) 9 (2021); 100053, 19

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
ARAS, autosomal recessive alport syndrome ; AS, alport syndrome ; Alport syndrome ; BSA, bovine serum albumin ; Collagen-IV ; EM, electron microscopy ; ESRD, end stage renal disease ; GBM, glomerular basement membrane ; Glomerular basement membrane ; Glycine missense mutation ; Kidney disease ; Mouse model ; PAS, periodic acid schiff ; TBM, tubular basement membrane ; TGF-b1, transforming growth factor beta1 ; UPR, unfolded protein response.

Sažetak
Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-chains of type-IV collagen, the most abundant component of the extracellular glomerular basement membrane (GBM). Currently most AS mouse models are knockout models for one of the collagen-IV genes. In contrast, about half of AS patients have missense mutations, with single aminoacid substitutions of glycine being the most common. The only mouse model for AS with a homozygous knockin missense mutation, Col4a3- p.Gly1332Glu, was partly described before by our group. Here, a detailed in-depth description of the same mouse is presented, along with another compound heterozygous mouse that carries the glycine substitution in trans with a knockout allele. Both mice recapitulate essential features of AS, including shorten lifespan by 30-35%, increased proteinuria, increased serum urea and creatinine, pathognomonic alternate GBM thinning and thickening, and podocyte foot process effacement. Notably, glomeruli and tubuli respond differently to mutant collagen-IV protomers, with reduced expression in tubules but apparently normal in glomeruli. However, equally important is the fact that in the glomeruli the mutant α3-chain as well as the normal α4/α5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35 kDa C-terminal fragment. These mouse models represent a good tool for better understanding the spectrum of molecular mechanisms governing collagen-IV nephropathies and could be used for pre-clinical studies aimed at better treatments for AS.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

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