Sugar coupled to protein causes kidneys to save water

Giel Hendriks discovered that the linking of sugars to the protein aquaporin-2 (AQP2) is necessary for the transport of water channels to the cell surfaces in the kidneys. If the protein is not linked to a sugar, it still forms functional water channels. However, these channels no longer end up at the cell surface where they need to do their work.

Kidneys extract water containing dissolved waste substances from the blood. Each day human kidneys produced about 180 litres of this so-called pro-urine. The excretion of all of this fluid would rapidly result in dehydration and eventual death. Therefore with the help of the water channels, the body returns about 99% of this water from the pro-urine to the kidney tissue. As a result of this a person only loses about 1.5 litres of urine per day.

The protein aquaporin-2 regulates a significant part of this water reuse. This protein forms water channels. These are transported from small storage vesicles to the cell surface, where they can collect the water and return it to the kidney tissue.

Mutations in AQP2 give rise to the disease nephrogenic diabetes insipidus (NDI). Patients with this disease lose 15 to 20 litres of urine per day. Knowing how AQP2 is transported to the cell surface and how it works there, is a prerequisite for developing a treatment for this disease.

In addition to the effect of sugars, Hendriks also studied the role of the small signalling protein ubiquitin in the functioning of AQP2. Ubiquitin ensures the breakdown of proteins and is important for quality control during the production of new proteins. Hendriks isolated AQP2 proteins to which a single ubiquitin was bound. Separating the proteins on the cell surface from those inside the cell revealed that only AQP2 with a single ubiquitin is located on the cell surface. The role of this coupling in the functioning of the protein will be investigated in a follow-up study by the Utrecht group.

Finally, the researchers isolated a new protein from a mouse kidney, AQP2-BP that directly binds to AQP2. Up until now no proteins capable of binding to AQP2 were known. By inserting both proteins in kidney cells, Hendriks discovered that AQP2-BP is important for the production of the useful protein AQP2.