Fruit Flies Can Model Kidney Disease
Research has shown that Drosophila (the genus to which fruit flies belong) can effectively model the genes responsible for genetic kidney disease in humans. The study, published in Human Molecular Genetics, has shown that the majority of genes associated with Nephrotic Syndrome (NS) in humans are also pivotal in Drosophila renal function, validating transgenic flies as accurate pre-clinical models.
NS is a condition made up of a number of symptoms, all of which indicate kidney damage. These symptoms include increased protein levels in urine and correspondingly decreased blood protein concentrations, elevated cholesterol levels, and swelling. Previous studies have managed to identify more than 40 distinct genes in humans which are linked to genetic kidney disease, but our understanding of their precise roles in kidney function is very limited.
To try to improve this understanding, the team from the Children’s National Health System systematically studied genes within the Drosophila model associated with NS. This included 7 genes with renal function which have never been analysed in a preclinical model before.
“85% of these genes are required for nephrocyte function, suggesting that a majority of human genes known to be associated with NS play conserved roles in renal function from flies to humans,” said Zhe Han, Ph.D., senior author of the paper and Associate Professor at the Centre for Cancer and Immunology Research at Children’s National. “To hone in on functional conservation, we focused on Cindr, the fly’s version of the human NS gene, CD2AP. Silencing Cindr in nephrocytes led to dramatic impairments in nephrocyte function, shortened their life span, collapsed nephrocyte lacunar channels – the fly’s nutrient circulatory system – and effaced nephrocyte slit diaphragms, which diminished filtration function.”
To validate that the phenotypes being examined were relevant to human NS studies, the team expressed the wild-type, functional human CD2AP gene within the model. Introduction of the gene reversed the renal damage being observed. When they expressed a mutant allele from a human sample with CD2AP-associated NS, the renal damage remained unchanged.
As a result of these findings, the team were able to conclude that the Drosophila model was an effective and accurate model of human kidney disease. The model could therefore be used to identify molecular mechanisms with the most clinical relevance, or to help us understand the pathogenesis of different monogenic forms of NS.
“This is a landmark paper for using the fly to study genetic kidney diseases,” Dr. Han said. “For the first time, we realized that the functions of essential kidney genes could be so similar from the flies to humans.”
In future, it may be possible to create personalised in vivo models for genetic renal diseases by using patient-specific mutations. These models would be ideal platforms for identifying new genetic treatments and validating potential therapeutic options.