A New 3-D Model Sheds Light On The Function Of Sugar In Polycystic Kidney Disease

A National Institutes of Health-supported research team has discovered a novel way to better understanding the biology of polycystic kidney disease (PKD), a potentially fatal hereditary illness that affects millions of people worldwide.

 Scientists used two methods for modeling the condition — organ-in-a-dish and organ-on-a-chip technologies — to demonstrate the involvement of glucose, a chemical usually found in blood, in the formation of PKD cysts. The findings, published in Nature Communications, may pave the door for new approaches to evaluate and develop medicines for PKD and maybe other disorders.

An organ-in-a-dish, also known as an organoid, is a small model of an organ developed in a laboratory dish. It can imitate important structural and functional properties of human organs.

Organs-on-a-chip, also known as tissue chips, are more advanced three-dimensional models with channels and live cells that try to imitate organ and tissue structure and environment.

The National Center for Advancing Translational Sciences (NCATS) research programs of the NIH explore these technologies as human cell-based methods to studying illness and better predicting whether medications would be safe or hazardous in humans.

One significant finding from the study:

Sugar appears to have a role in the production of fluid-filled cysts, which are a characteristic of PKD. In humans, these cysts develop large enough to compromise kidney function and eventually cause the kidneys to fail, needing dialysis or transplantation.

Nature Communications reported the findings. Sienna Li and Ramila Gulieva are co-lead authors and research professionals in the lab of Benjamin Freedman, a nephrology investigator at the University of Washington School of Medicine.

Freedman has been studying PKD in organoids produced from pluripotent stem cells for many years. Organoids resemble small kidneys in that they include filtering cells linked by tubes and may respond to infection and treatments in ways similar to human kidneys.

The experiment study results:

Although this team can develop organoids that give birth to PKD cysts, the methods by which those cysts originate are unknown. The researchers focused on how the movement of fluid within the kidney contributes to PKD in this study by developing a new tool that combined a kidney organoid with a microfluidic chip. This allowed water, sugar, amino acids, and other nutrients to flow across organoids that had been genetically modified to imitate PKD.

Mini–kidney tube structures have sugar receptors (red, upper left) and form outward-facing polycystic kidney disease cysts (center image), which swell by taking in sugar (green, lower right).University of Washington

The cells lining the walls of the PKD cysts faced outward as they stretched and inflated in the chips, so the tops of the cells were on the outside of the cysts. This inverted orientation – these cells would face inward in functioning kidneys – shows that cysts grow by attracting sugar-rich fluid rather than secreting it.

When the researchers gave fluorescent glucose to mice with PKD, they discovered that the glucose was also taken up by the mouse cysts. Freedman suggested that the tubules in mice, like those in organoids, take in fluid. The kidney grows in size, and when the tubules expand to accommodate the enlargement, cysts develop.

The experiment's findings are relevant since there is a class of compounds that limit sugar absorption in the kidneys and are appealing treatments for a variety of illnesses.

Researcher's final statement:

The researchers demonstrated that mimicking fluid movement is critical to making this system more match the environment in the PKD kidney. By combining the two technologies, tissue chip technology becomes more adaptive to drug discovery and development, allowing researchers to capitalize on the capabilities of both platforms. This has great promise for future research into other disorders.