For over 30 years, endocrinologist Maria-Christina Zennaro, Inserm research director at the Paris Cardiovascular Research Center, has endeavored to better understand the causes of high blood pressure. Her latest project, ENSAT-HT, which federates European research forces, has received an Étoiles de l’Europe award.
Hypertension, which kills 11 million people each year worldwide, exists in more than one form. The most common, called « primary hypertension », has no known specific cause. « Secondary hypertension », which affects 5 to 15% of people with hypertension, may be the consequence of endocrine dysfunction, in which aldosterone plays a particular role. This hormone is the focus of research by Maria-Christina Zennaro, Inserm research director at the Paris Cardiovascular Research Center (Parcc). With the European project ENSAT-HT, the endocrinologist wishes to improve the diagnosis of these forms of hypertension in order to optimize their treatment. Her initiative has received the Étoiles de l’Europe trophy, an award honoring « French teams who choose Europe for research and innovation ». A selection criterion that is patently obvious for Zennaro.
« A European and a researcher, I’ve the impression that I’ve always been like this. Originally from Upper-Adige (South Tyrol) in Italy, I began studying medicine in Innsbruck, Austria, 50 miles from home. I immediately wanted to do medical research, even though endocrinology is more about chance discoveries, » she explains. After two years in Innsbruck, she enrolled at Padua University where she joined the Endocrinology Department. There she discovered that « this discipline really lends itself to research, with its complex system of communication between different organs by hormones. For example, when blood pressure decreases, a signal is sent to the kidneys, which ‘inform’ the adrenal glands located just above them. The adrenal glands then secrete aldosterone, which promotes the retention of salt and water in the blood, increasing blood pressure. »
With her unabated fascination with the subject and after receiving her medical diploma in 1989, she chose to focus on aldosterone. The following year, she joined the team of Florent Soubrier at Pierre Corvol’s laboratory at Collège de France, Paris, in order to search for mutations in the aldosterone receptor gene that are the cause of a rare disease, pseudohypoaldosteronism type I (PHA1), which affected a family receiving follow-up in Padua. « I was supposed to work there for one year, but stayed for four years and did my science dissertation, she remembers. I characterized the gene of that receptor. It was an exciting time! »
Understanding Primary Hyperaldosteronism…
From 1995, she continued her research into this rare disease and more broadly into the aldosterone receptor in the group of Marc Lombès at Nicolette Farman’s laboratory at Bichat Hospital, Paris. « That was the team in which I was recruited by Inserm in 1998, she points out. I think it’s thanks to such an environment, with a female researcher as head of unit, that I always found it normal for a woman to lead a team. » On the scientific side, she identified several mutations making it possible to distinguish the less severe form of PHA1, which affects the kidneys, from the generalized form, which is synonymous with life-long treatment. She also showed that the aldosterone receptor plays a role in glucocorticoid hormone-induced adipogenesis. « Without abandoning my research into PHA1, which remains the leitmotif of my career, I wanted to do more in-depth genetic research, particularly into primary aldosteronism (PA), she continues. This autonomous overproduction of aldosterone is the leading cause of secondary hypertension. So in 2004 I returned to Collège de France to join Xavier Jeunemaitre’s team, which enabled me to also start a clinical genetics activity at Hôpital Européen Georges-Pompidou. » Research into PA that she did from 2009 at Parcc, where she created her own team in 2014. Through this, Zennaro contributed to the discovery of many mutated genes, including some associated with a form of PA that occurs during puberty, pregnancy, and menopause. She also identified another gene whose mutations lead to early hereditary PA. Finally, she described susceptibility to developing PA that is related to common genetic variations, which could play a role in hypertension in the general population.
...To Facilitate Its Diagnosis
Despite these advances, the diagnosis of PA and other forms of secondary hypertension remains long and laborious, which delays their treatment. However, ENSAT-HT could prove to be a game-changer. The 18 teams coordinated by Zennaro have used artificial intelligence to integrate multiple « omics » data (i.e. on a large scale) from patient plasma and urine samples, and have identified biomarkers of different forms of hypertension. « Leading so many scientists to feel that they are stakeholders in the same adventure hasn’t always been easy, but I’ve learned a lot! » assures the researcher whose enthusiasm for this public health challenge remains unabated. After validating this diagnostic approach in 2,000 people with hypertension of unknown origin, she is now coordinating its application to improve the identification and treatment of the endocrine forms of hypertension. « I’d like one day for any community doctor to be able to prescribe simple tests to diagnose their patient’s type of hypertension and apply the most appropriate treatment, she shares. While acknowledging: It may take some time… Even if it’s just getting PA diagnosed more quickly, I’d be delighted! »
Maria-Christina Zennaro, Xavier Jeunemaitre : Centre de recherche cardiovasculaire de Paris (Parcc – unité 970 Inserm/Université Paris Cité)
Florent Soubrier : Unité de recherche sur les maladies cardiovasculaires du métabolisme et de la nutrition (ICAN – unité 1166 Inserm/Sorbonne Université)