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A Potential Explanation for Differences in Susceptibility to Kidney Complications of Diabetes

New research in mice has identified a genetic factor that might help explain why some people with diabetes are more prone than others to kidney complications of the disease. Between 10 and 30 percent of people with either type 1 or type 2 diabetes develop diabetic kidney disease (DKD), making diabetes a major risk factor for loss of kidney function. But because most people with diabetes do not develop DKD, there is considerable interest in understanding what puts some people at higher risk than others. One of the early events in development of DKD is loss of a type of kidney cells called podocytes, which act as the first filter for blood. These cells permit water, salts, and other small molecules in the blood to exit the bloodstream, while blocking larger compounds like proteins from coming along for the ride. When podocytes disappear, protein levels start to fall in the blood, and rise in the urine—hallmarks of kidney disease.

Podocytes also disappear in a strain of mice that are susceptible to DKD, but they remain present in a different strain of mice with kidneys that stay healthy even when the animals have diabetes. Looking for differences between the two strains, researchers noticed that the mice that lose their podocytes after developing diabetes were producing more of a protein called xanthine oxidoreductase (Xor). They found that this was due to a difference in a region of DNA that helps regulate how much of the protein is produced when glucose levels rise (as in diabetes). To see if this difference was important, the scientists created a mouse strain that had the genetic predisposition to create excess Xor but was otherwise identical to the DKD-resistant animals. When experimentally given diabetes, these mice rapidly lost their podocytes, suggesting that elevated Xor might be an important factor in contributing to DKD. If levels of Xor turn out to have a similar impact on podocytes and kidney health in people with diabetes, future work might focus on trying to develop a medication that can safely inhibit Xor’s effects in hopes of one day preventing DKD or slowing its progression in those at risk for the disease.

Wang Q, Qi H, Wu Y,…Daehn I. Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR. Nat Metab 5: 607-625, 2023.
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