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New technologies help uncover an unexpected role of glucose in polycystic kidney disease

Using an innovative new method to simulate a micro-environment within the kidney, scientists have discovered that glucose absorption contributes to the growth of cysts in polycystic kidney disease (PKD). PKD is a genetic disorder that causes many fluid-filled cysts to grow in a person’s kidneys, leading to chronic kidney disease, high blood pressure, and often kidney failure. When waste products are initially filtered out of the blood in the kidney, water and important nutrients go along for the ride. These valuable materials are largely reabsorbed as they pass through tiny structures called tubules. It is within these tubules that cysts form in PKD. Because tubules are enclosed within the kidney, it is difficult to research the mechanisms behind PKD cyst formation in humans or using animal models. Previous studies have led to the development of microscopic structures outside of a living organism, called kidney organoids, which contain not only the tubules, but the other components of the blood filtration system. Importantly, kidney organoids from cells with PKD-causing mutations develop tubular cysts, just as they would in a person. Organoids are typically grown in static fluid conditions, but because of the constant exchange of fluid within the kidney, an understanding of the impact of liquid flow on PKD organoids is needed. This understanding could provide needed insight into the mechanisms of cyst formation in the kidney.

For this research study, scientists grew organoids and attached them to special microscope slides called chips that contain small channels to provide a fluid-flow environment similar to that of a living kidney. They observed via microscope that the PKD organoid cysts grew twice as fast in fluid-flow conditions as they did when the liquid around them was motionless. The researchers discovered that cyst growth rate was closely linked to their exposure to glucose, a nutrient normally reabsorbed by the tubules. They found that the PKD cysts absorbed and expanded in response to glucose and subsequently showed that this expansion could be reversed with the use of a drug that inhibits tubular reabsorption of glucose. Equipped with the insight gained from the PKD organoid on chip model, the researchers were then able to confirm the uptake of fluorescent glucose in PKD cysts within the kidneys of a PKD mouse model, suggesting that the same phenomenon occurs in living PKD kidneys.

The novel organoid-on-chip PKD model used in this study provided new insight into the impact of fluid flow and glucose uptake on the formation of PKD cysts within the kidney. With further research, safety studies, and clinical trials, these findings suggest that glucose uptake-inhibiting drugs might one day help prevent the progression of PKD in people with the disease.

Li SR, Gulieva RE, Helms L,…Freedman BS. Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease. Nat Commun 13: 7918, 2022.

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