Polycystic kidney disease or polycystic kidney is a pathology that affects the kidneys, the organs that filter the blood, purifying it of impurities, produce urine, keep blood pressure under control and, in general, maintain the water-salt balance of the body.

There are two forms of polycystic kidney disease: the autosomal dominant form, which is one of the most frequent genetic diseases and afflicts 1 person out of 400-1000, and the autosomal recessive form, that is much rarer.

On the occasion of World Kidney Day, we interviewed Doctor Alessandra Boletta, group leader of the Cystic Kidney Disorders Unit at the IRCCS Ospedale San Raffaele, on the polycystic kidney disease on its autosomal dominant form and its possible treatments.

 

Polycystic kidney disease and cellular metabolism

In the autosomal dominant form of polycystic kidney disease, cells in the renal tubules, where urine is produced, proliferate till they form cysts, or fluid-filled spheres.

This form of the disease is caused by mutations in the PKD1 and PKD2 genes. An ill parent, that has the mutation, has a 50% fo probability of transmitting the disease to both of the children, and this is the reason why it is called “autosomal dominant”.

PKD1 and PKD2 genes provide cells with instructions for synthesizing polycystins. These are proteins that are normally involved in regulating cell morphology and maintaining the correct diameter of the renal tubule. In particular, polycystins are found in a cellular organelle called the primary cilium.

The primary cilium resembles an antenna on the surface of many types of cells, including neurons, blood vessel cells, and renal tubule cells. One of the first descriptions of the primary cilium in mammalian cells dates back to 1898 by the German anatomist Karl Wilhelm Zimmermann, but the functions of this organelle are still being studied intensively by researchers.

“Today we think that the cilium senses both mechanical stimuli, such as the flow of liquids, and chemical stimuli such as messenger molecules present in the body’s fluids. It is still unclear what are the consequences of the sensory function of the primary cilium inside the renal tubule cell. In this context, in recent years my laboratory has revealed a link between the ability of the primary cilium to perceive the availability of nutrients outside the cell and the regulation of cellular metabolism, that is the set of processes that consume and generate energy,” as Boletta explains.

The doctor’s group has in fact observed that the primary cilium lengthens looking for nutrients when their concentration in the environment outside the cell is very low; instead, if the availability of nutrients is increased, the cilium shortens.

These changes in the length of the cilium result in changes in cellular metabolism, particularly involving the mitochondria, the organelles that produce energy. The cilium would function as an antenna that catches information about the availability of energy to transmit it to the mitochondria, in a way that is only partially understood, thus regulating cellular metabolism.

“We already knew, from previous work by our group, that mitochondria are highly altered in polycystic kidney disease. This motivated us to study the mechanisms of communication between the primary cilium and the mitochondria and what the implications are not only for the single cell, but for the entire organism. This research is important to lay the foundations for finding new targets for the treatment not only of polycystic kidney disease, but of ciliopathies in general, that is, all those diseases in which the proteins of the primary cilium are mutated,” continues the Doctor. “In particular, renal ciliopathies represent the most frequent cause of genetic diseases that affect the kidney.”

 

Polycystic kidney disease and possible therapeutic strategies

Today, the only drug approved for the treatment of polycystic kidney disease is tolvaptan, an antagonist of the vasopressin receptor, the hormone that regulates thirst. The inhibitory action of tolvaptan reduces the production of cAMP, a small molecule that stimulates the proliferation of renal tubule cells, and this treatment therefore results in reduced cell proliferation and therefore reduced growth of renal cysts.

In light of the continuous research of new treatment strategies for polycystic kidney disease, Dr. Boletta's group is testing the use of a compound called 2-DG to slow down the metabolism of renal tubule cells and therefore their proliferation.

"Ten years ago we discovered that polycystic kidney disease mainly uses glucose to generate energy in a metabolic process called glycolysis. The idea is that if glycolysis is inhibited or slowed down, then the cell lacks the energy needed to proliferate and this should slow the growth of renal cysts. We therefore thought of slowing down the use of glucose by replacing it with a molecule called 2-DG. 2-DG resembles glucose, but, unlike the latter, it cannot be used as an energy source in glycolysis”, explains the Doctor.

This ability of 2-DG to slow down cellular metabolism had already been tested in the past in other pathologies of tumor origin.

“Starting from previous research in the oncology field, we began to consider 2-DG for the treatment of polycystic kidney disease. And it is precisely by studying the action of 2-DG that we have understood something more about the metabolism of polycystic kidney disease and also the involvement of the primary cilium in its regulation” adds Boletta.

It is important to remember that, unlike a tumor, in polycystic kidney disease the renal tubule cells proliferate very slowly and it takes about fifty years for the organ’s functioning to be compromised. In fact, in humans, polycystic kidney disease does not transform into a malignant tumor of the kidney.

“This difference between polycystic kidney disease and tumor is very relevant and opens up new perspectives and research questions. For example, what can we learn from the metabolic mechanisms underlying cilium diseases such as polycystic kidney disease that can help us, in turn, better understand the mechanisms underlying tumors? How does studying one pathology help us understand, and therefore treat, the other? Basic research and more translational research, that is, aimed at the concrete development of therapies, thus proceed together, influencing each other, to answer these and other questions", concludes the Doctor.