Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background
Open Access
- 31 December 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 9 (1), 1-15
- https://doi.org/10.1038/s41598-019-56837-6
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 modified genetically. We have identified a point mutation in Col4a4 in mice where disease is modified by strain background, providing further evidence of the genetic modification 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 identified early differences in disease progression, including expression of podocyte-specific genes and podocyte morphology. In C57BL/6J mice podocyte effacement 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 find that there is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.Funding Information
- RCUK | Medical Research Council (MC U142684172)
This publication has 56 references indexed in Scilit:
- Albuminuria is associated with too few glomeruli and too much testosteroneKidney International, 2013
- Endocytosis of Albumin by Podocytes Elicits an Inflammatory Response and Induces Apoptotic Cell DeathPLOS ONE, 2013
- Upregulated Expression of Integrin α1 in Mesangial Cells and Integrin α3 and Vimentin in Podocytes of Col4a3-Null (Alport) MicePLOS ONE, 2012
- Mouse genomic variation and its effect on phenotypes and gene regulationNature, 2011
- MYO1EMutations and Childhood Familial Focal Segmental GlomerulosclerosisThe New England Journal of Medicine, 2011
- Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in GlomerulonephritisAmerican Journal of Nephrology, 2010
- Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndromeJCI Insight, 2010
- Proteinuria precedes podocyte abnormalities inLamb2-/- mice, implicating the glomerular basement membrane as an albumin barrierJCI Insight, 2006
- The podocyte's response to injury: Role in proteinuria and glomerulosclerosisKidney International, 2006
- Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome.The Journal of cell biology, 1996