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.