Research into a rare kidney disease reveals a mechanism responsible for hypertension

Research into a rare kidney disease has shed important light on a possible way to tackle high blood pressure, a risk factor for the circulatory system that in Italy alone affects a third of the adult population.

Luca Rampoldi

The study, financed by Telethon and published in Nature Medicine* by the Luca Rampoldi team of the Telethon Dulbecco Institute at the San Raffaele Hospital in Milan, has highlighted a mechanism linking uromodulin, a protein present in urine, with a higher risk of developing high blood pressure and kidney damage.

For years now, this research group has been studying a rare kidney disease caused by defects in the gene containing the information for uromodulin, the most abundant protein normally present in urine. Although this protein was discovered over 50 years ago, its biological function remains a mystery.This work began with the discovery that a number of common variants of the uromodulin gene, specifically in the region regulating expression and thus production, are associated with a higher risk of developing hypertension and kidney damage during life.

In this study, the Telethon researchers discovered the biological bases of this connection, thanks to the complex work conducted and coordinated by the team headed by Dr. Luca Rampoldi, together with the team of Prof. Olivier Devuyst of the University of Zurich.The work combined basic research study on cellular and animal models and clinical research study on groups of patients. A number of specialists were brought in to collaborate, including, in the clinical area, the team led by Prof. Paolo Manunta of San Raffaele University, in the area of kidney disease, Dr. Maria Pia Rastaldi of the Policlinico di Milano Hospital, and in the area of epidemiology studies, with a group of Swiss universities (Bern, Geneva, Lausanne, Zurich).

Dr. Rampoldi, head of the Molecular genetics of kidney disease Unit at the San Raffaele Institute, explained: «By analysing dozens of renal biopsies and hundreds of urine samples from people with normal blood pressure and kidney function, we observed that uromodulin levels varied based on specific ADN sequences. Specifically, those people with variants liable to place them at risk of hypertension or kidney damage produced larger amounts of uromodulin than carriers of the protective variants. We therefore posed the question of the way in which a high expression of the uromodulin gene could lead to an increased risk of developing hypertension or kidney disease during life».Work on mouse models showed that an increase in the production of uromodulin leads to hypertension at a young age, but also that a reduction in the salt content of the patient's diet is sufficient to restore normal blood pressure values. «Our hypothesis – continued the researcher – is that this protein helps the reabsorption of salt and water at renal level, by means of a mechanism we have partially identified. High levels of expression cause greater reabsorption of sodium, which boosts the action of a specific transport protein located in the kidney: this leads to an increase in blood pressure. How is this demonstrated? By administering a potent diuretic targeted at this reabsorption system, we found that it had a greater effect on blood pressure in animals that produced larger amounts of uromodulin».

Professor Paolo Manunta, a nephrologist and Director of the Specialised Nephrology School of the Vita-Salute San Raffaele University, added that «The same mechanism appears to be present in humans: hypertension sufferers treated with the same diuretic showed a significant reduction in blood pressure only if they were carriers of the genetic variants associated with a higher expression of uromodulin».Another important aspect that emerged from the study was that high levels of uromodulin expressions cause kidney lesions at an advanced age.

«This study is a clear example of translational research – commented Professor Paolo Manunta – because the results obtained on the experimental models have been applied to clinical practice regarding patients with high blood pressure, thanks to the interaction between researchers and doctors that is a characteristic of San Raffaele hospital. In keeping with an increasingly personalised approach to medicine, this work shows how genetics can be of assistance in choosing specific treatments for high blood pressure that are more effective and have fewer side effects».«Our study – concluded Rampoldi – makes a significant contribution not only to understanding how our kidneys work, but also to shedding light on the complex mechanisms underlying common illnesses such as high blood pressure and chronic kidney disease, as well as suggesting interesting applications on a large scale: it paves the way to the development of medicines for high blood pressure able to target uromodulin or other molecules involved in the mechanism governed by this protein, regarding which there is still much to be discovered».

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