title: Choosing a mouse model to study the molecular pathobiology of Alport glomerulonephritis.
abstract: Alport syndrome, caused by mutations that interfere with the normal assembly of the alpha3alpha4alpha5(IV) collagen network in the glomerular basement membrane (GBM), is the most common inherited glomerular disease leading to renal failure. A detailed knowledge of the underlying pathogenic mechanisms is necessary for developing new, more specific, and effective therapeutic strategies aimed at delaying the onset and slowing disease progression. Studies of several dog and mouse models of Alport syndrome have significantly enhanced our understanding of the disease mechanisms and provided systems for testing potential therapies. In the most widely used Col4a3-/- mouse models of autosomal-recessive Alport syndrome (ARAS), the genetic background strongly affects renal survival. One contributing factor may be the strong ectopic deposition of alpha5alpha6(IV) collagen in the GBM of Col4a3-/- mice on the C57BL/6J background, which is almost undetectable on the 129/Sv background. This isoform 'switch' has not been observed in human ARAS, although it had been reported in the dog model of ARAS. In human patients as well as dog and mouse models of X-linked Alport syndrome, the alpha3-alpha6(IV) collagen chains are absent from the GBM. These biochemical differences among Alport animal models provide an opportunity to determine how the molecular makeup of the GBM affects the glomerular function. At the same time, potentially confounding influences of characteristics unique to a particular strain or model should be carefully considered in the design of studies aiming to define key events underlying the pathobiology of Alport glomerular disease.
authors.affiliation: Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska, USA. Cosgrove@boystown.org
authors.forename: D
authors.initials: D
authors.lastname: Cosgrove
authors.forename: R
authors.initials: R
authors.lastname: Kalluri
authors.forename: J H
authors.initials: JH
authors.lastname: Miner
authors.forename: Y
authors.initials: Y
authors.lastname: Segal
authors.forename: D-B
authors.initials: DB
authors.lastname: Borza
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D051379:Mice; D009394:Nephritis, Hereditary / Q000235:genetics*