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 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.

Automated predictive analytics tool for rainfall forecasting

“…Water is essential to all livelihood and all civil and industrial applications. Accurate rainfall prediction is important for planning and scheduling of these activities 9 . There is numerous literature available on different rainfall prediction approaches including but not limited to data mining, artificial neural networks and machine learning 10 .…”

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

“…These model mice led important aspects of the renal disease. Whereas, there are some significant differences depend on genetic background in Alport syndrome model mice 9 , 13 , 14 . For example, 129X1/Sv or C57BL/6 was different patterns of disease progression in Col4 α 3 -/- mice 15 .…”

Creation of X-linked Alport Syndrome Rat Model with Col4a5 Deficiency

“…4 Several mouse models in Col4α3, Col4α4 , and Col4α5 mutation have been known and characterized. 6-10, 13 Col4α3 -/- or Col4α4 -/- mice are well used for studying treatments of Alport syndrome compared to Col4α5 -/Y mice. 28-31 Because, a survival ratio of Col4α5 -/Y mice was so diffusive ranged from 6 to 34 weeks, 9 in contrast, those of Col4α3 -/- or Col4α4 -/- mice were more uniform (from 13 to 26 weeks).…”

“…Whereas, there are some significant differences depend on genetic background in Alport syndrome model mice. 8, 12, 13 For example, 129×1/Sv or C57BL/6 was different patterns of disease progression in Col4α3 -/- mice. 14 Indeed, in the human patients, the disease progression and effects of pharmacological therapy were shown to genetic variability.…”