Polycystic kidney disease (PKD) is an inherited disorder that affects more than 600,000 people in the United States. The disease causes fluid-filled cysts which can affect kidney functioning and lead to kidney failure, an outcome requiring dialysis or transplant. Currently, there is no cure for PKD.
ISCRM faculty member Benjamin Freedman, PhD, Associate Professor of Medicine/Nephrology uses organoid technology to study how PKD originates and to test potential treatments. While Freedman’s team can grow stem cell-derived organoids with PKD cysts, how exactly those cysts form is still not well understood.
Now, a paper from the Freedman Lab, published in Nature Communications, reveals a surprising finding about the way cysts form in PKD organoids, a discovery that could have clinical implications. The co-lead authors of the paper are Sienna Li and Ramila Gulieva, research scientists in the Freedman Lab. Jonathan Himmelfarb, MD, who was the Inaugural Director of UW Medicine’s Kidney Research Institute, is a co-senior author of the paper.
While it is known that genetics help explain whether a patient might develop PKD, Freedman and his team are interested in how the disease takes hold at the molecular level. In their investigation, they focused on how the flow of fluid within the kidney contributes to PKD – at least in organoids.
To derive new insights on the effects of flow on PKD, the researchers invented a new tool called a human kidney organoid on a chip – a microphysiological system that allows a fluidic combination of water, sugar, amino acids, and other nutrients to flow over the organoids, which were gene-edited to mimic PKD.
“We were expecting the PKD cysts in the organoids to get worse under flow, because the disease is associated with the physiological flow rates that we were exploring,” explains Freedman. “The surprising part was that the process of cyst swelling involved absorption – the intake of fluid inwards through cells, from outside the cyst. That’s the opposite of what is commonly thought, which is that cysts form by pushing fluid outwards through cells. It’s a whole new way of thinking about cyst formation.”
Specifically, the researchers observed in the chips that the cells lining the walls of the PKD cysts faced outward as they stretched and swelled so that the tops of the cells were on the outside of the cysts. This inverted arrangement (these cells would be facing inward in living kidneys) suggests that cysts grow by pulling in sugar-rich fluid, not by secreting the liquid.
Freedman emphasizes two important insights from the study. First, the observation gives the field more information about the means by which cysts form in organoids, a finding that will have to tested further in in vivo models. Second, the fact that sugar levels drive cyst development points to new potential therapeutic options.
“The results of the experiment are significant because there is a whole class of molecules that block sugar uptake in the kidneys and are attractive therapeutics for a number of conditions,” says Freedman. “They haven’t been tested yet, but we view this as a proof-of-concept that these drugs could potentially help PKD patients.”
Acknowledgements:
The work was supported by the National Institutes of Health (UG3TR002158, UG3TR003288,
UG3TR000504, K01DK102826, R01DK117914, U01DK127553, UC2DK126006, U01HL152401), a Novo
Nordisk sponsored research award, a gift from the Northwest Kidney Centers to the Kidney Research
Institute, the Lara Nowak Macklin Research Fund, a gift from the Mount Baker Foundation, and startup
funds from the University of Washington.