A new mouse model of Alport syndrome with slower disease progression may provide a better way to study the disease’s underlying mechanisms and potential therapies, a recent study suggests.
The work confirmed the existence of additional genetic factors — potentially the MYO1E gene — influencing Alport’s progression, associated with differences in gene activity and a delayed inflammatory response.
Data showed that higher urinary levels of monocyte chemoattractant protein-1 (MCP-1; an inflammatory marker) and kidney injury molecule 1 (KIM-1; a marker of kidney damage) precede kidney failure, suggesting that these proteins may be used as urinary biomarkers of disease progression.
The study, “Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background,” was published in the journal Scientific Reports.
Alport syndrome is caused by mutations in the COL4A3, COL4A4, and COL4A5 genes, leading to defects in type IV collagen, a major structural protein essential for the normal functioning of the kidney, inner ear, and eye.
In the kidney, type IV collagen is only produced by specialized cells called podocytes. The production of a defective protein leads to changes in the glomerular basement membrane (GBM) — which has a key role in the kidney’s filtration barrier — as well as proteinuria (proteins in the urine), and hematuria (blood in the urine). All of these are markers of kidney damage.
Data from Alport patients and animal models show that “the progression of disease can vary greatly and can be modified genetically,” the researchers wrote.
The genetic background of a mouse model of a disease comprises the normal genetic makeup (all its genes) except the mutated gene of interest and a very small number of other genetic changes. These additional genetic mutations, despite being non-causative of any disease, may influence the disease’s features and progression.
While previous studies suggested that Alport mice with a specific genetic background called C57BL/6J have slower disease progression than others, the underlying mechanisms accounting for the difference remain unknown.
Researchers in the U.K. identified a new COL4A4 mutation leading to Alport syndrome in mice, and compared the features of these mutated mice with two different genetic backgrounds, C57BL/6J and C3H.
Results showed there were significant disease-related and molecular differences between the two strains of mice.
Notably, C57BL/6J mice had a slower Alport progression, with kidney failure delayed to several months, instead of seven weeks. This confirmed the protective nature of C57BL/6J genetic background in mice with Alport-causing mutations, and the existence of additional genetic factors influencing disease progression.
“The slower disease progression has allowed us to begin dissecting the [underlying mechanisms] of murine Alport Syndrome in detail,” the researchers wrote.
Examination of disease-related features, kidney function, and gene activity showed that disease progression in the two strains of mice starts to differ by 4 weeks of age, after the presence of GBM changes and proteinuria.
C57BL/6J mice had a delayed inflammatory response, less damage to the kidney tubules, and prolonged podocyte health. This reflected differences in the activity of podocyte-specific genes and podocyte shape, as well as lower levels of inflammatory (MCP-1 and TNF-alpha) and kidney damage (KIM-1) markers.
Increasing levels of MCP-1 and KIM-1 in the urine preceded loss of kidney function, suggesting that “these may prove to be useful urinary biomarkers of disease progression” in Alport syndrome, the researchers said.
In an attempt to identify potential genetic modifiers of disease progression in C57BL/6J mice, the team conducted a preliminary genetic comparison of C57BL/6J with C3H and two other genetic backgrounds present in Alport mouse models.
Among several mutations identified exclusively on the C57BL/6J background, the most relevant one was in the MYO1E gene, which contains the instructions to produce the myosin 1e protein.
In the kidney, myosin 1e is produced by podocytes as a component of the kidney’s filtration barrier. MYO1E mutations have also been associated with kidney disease, and this gene was previously suggested to be a modifier of Alport syndrome in an affected family.
While the evidence suggests that this MYO1E mutation may contribute to C57BL/6J-specific slower disease progression, researchers said further studies are required to confirm the association.
“The relatively slow progressive disease present on the C57BL/6J background provides a greater window of opportunity for studying mechanisms and trialing therapeutic interventions, and indeed may better model the progression of AS symptoms in patients,” the researchers wrote.
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