New Paper from the McNagny Lab Reveals Mechanisms of Human Kidney Disease

The McNagny Laboratory Team

 

The McNagny Lab, whose current research is focused on stem cells and the underlying workings of immune response and chronic inflammation, has just published a new paper in Scientific Reports that offers exciting new avenues of inquiry for investigating the kidney disease, Focal Segmental Glomerular Sclerosis (FSGS).

In the paper, the team outlines how one bad copy of the stem cell gene, podocalyxin, can make mice highly sensitive to FSGS. A recent study has shown that people with only one good copy of the same gene are also prone to late-onset FSGS. “This makes our mouse an exquisitely accurate model of the disease,” McNagny says, “and what this indicates is that lowering the level of expression of podocalyxin through means besides mutation, like shedding in response to inflammatory disease, may enhance our susceptibility to FSGS.”

What is the significance of these findings? According to McNagny’s team, this raises an interesting idea in understanding kidney disease. “Not only does this tell us that expression alterations in podocalyxin may be responsible for a much larger percentage of kidney disease, we think our data is telling us that lower levels of this protein coupled with a secondary hit, such as exposure to drugs or infections, can set you up for FSGS.”

Currently, there is no cure for FSGS and the only way to diagnose it is an invasive kidney biopsy, but the insights provided by their new model offer an ideal opportunity to explore and test both novel therapeutics and avenues for treatment. And this extends beyond FSGS to the possible prevention of other types of kidney diseases. Because FSGS is one of the leading causes of end-stage kidney disease, the chance to better identify the early pathophysiological changes that occur in kidneys before the full-blown disease develops could have profound positive impacts on the design of new therapies and patient outcomes.

When asked what sparked this line of inquiry, the team’s answer encompassed so many of humanity’s small and large steps forward in science: it came down to a bit of serendipity and a bit of hard work. “Last year, a separate group described how having only one good copy of the podocalyxin gene lead to FSGS in humans,” says Ido Refaeli, the lead author of the study. “What was interesting to us was that our mice with only one copy of the gene have a very similar mutation but do not acquire kidney disease spontaneously. We decided to test the hypothesis that these mutations in podocalyxin lower an individual’s threshold for secondary insults and stresses. This proved true, insults that have no effect on normal mice cause full blown FSGS in our mice and it is quite likely a similar mechanism is also true for humans bearing these mutations.”

The next step for this research is to try to find biomarkers that can help scientists and physicians identify those people who are more likely to develop the disease. This would make early diagnosis easier while offering clues about novel avenues of treatment. These mice also provide an excellent model to test candidate therapies that could cure or slow the progression of kidney disease in people.

“We’ve already started looking at alterations in gene expression that occur before obvious symptoms of disease arise, and we’re seeing a fascinating shift in key biological pathways,” says McNagny. “We’re hoping this will give us more insights into how the disease starts and how we can halt or slow its progression.”

The McNagny lab’s work is an exciting example of what researchers are discovering and building on the leading edge of science. Dr. McNagny sums this up best when he says, “It’s a true example of how complicated biology can be, but also of how following the clues that lead off the path can bring you to a very important discovery.”

Learn more about the McNagny Lab

This work was generously supported by the Barbara Opperman Kidney Research Fund

Dr. Kelly McNagny is an immunologist and stem cell biologist and Professor in Medical Genetics with the School of Biomedical Engineering. He has trained in top labs in the US and Europe and is the Former Associate Scientific Director of the Canadian AllerGen Network Centre of Excellence.