Study Uncovers Regulators of Distal Nephron Function

Researchers at Massachusetts General Hospital (MGH) have identified two proteins that play key regulatory roles in kidney function, including  concentrating urine, regulating blood pressure, and controlling calcium and magnesium levels. The findings could contribute to novel therapeutic targets for kidney disease.

The kidney uses microscopic units called nephrons to carry out its functions in the body. These nephrons consist of different segments with distinct jobs, although how these segments form during development and how their function is maintained in adulthood is only partially understood.

The MGH team specifically investigated the formation and function of the distal nephron, which plays key roles in regulating electrolyte homeostasis and urinary concentration. Parts of the distal nephron have specific salt transporters, which are the main targets of medicine’s most effective diuretics, used in the treatment of hypertension and chronic kidney disease.

In a 2020 study, Alexander G. Marneros, MD, PhD, a physician-scientist at Mass General’s Cutaneous Biology Research Center and an associate professor of Dermatology at Harvard Medical School, found that AP-2β is required for the formation of the distal convoluted tubule, which is the segment of the distal nephron that is targeted by thiazide diuretics. This prompted him to question whether the closely related protein AP-2α also has a function in the kidney.

In the current study, published in Nature Communications, Marneros and colleagues found that the two very similar proteins regulate the function of two distinct segments of the distal nephron in mice. They report that, while AP-2β function in the kidney is required for survival by regulating the development and function of distal convoluted tubules, AP-2α is important for the proper function of a different segment of the distal nephron, called the collecting duct, which is involved in the kidney’s ability to concentrate urine. Notably, loss of even only half of AP-2β levels causes progressive kidney disease, whereas complete loss of AP-2α resulted in less severe kidney abnormalities.

“Inactivation of AP-2α in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult,” according to the paper. “Heterozygosity for AP-2β in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and β-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2β in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with β-catenin/mTOR hyperactivation, and early postnatal death.”

Marneros says the findings show AP-2α and AP-2β are important regulators of distinct segments of the distal nephron and are “important contributions” to the understanding of how specific segments of the kidney are regulated at the molecular level. A detailed understanding of the mechanisms that not only lead to the formation of distal nephron segments but also that maintain the proper function of these segments in the adult is important for future novel therapeutic approaches in the management of various kidney diseases, he adds.