Journal Article


Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

Abstract

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modifed genetically. We have identifed a point mutation in Col4a4 in mice where disease is modifed by strain background, providing further evidence of the genetic modifcation of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identifed early diferences in disease progression, including expression of podocyte-specifc genes and podocyte morphology. In C57BL/6J mice podocyte efacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We fnd that there is evidence of diferential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an infammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.

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Authors

Falcone, Sara
Wisby, Laura
Nicol, Thomas
Blease, Andrew
Starbuck, Becky
Parker, Andrew
Sanderson, Jeremy
Brown, Steve D.M.
Scudamore, Cheryl L.
Pusey, Charles D.
Tam, Frederick W.K.
Potter, Paul K.

Oxford Brookes departments

Department of Biological and Medical Sciences

Dates

Year of publication: 2019
Date of RADAR deposit: 2019-12-09


Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License


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