NGAL, a novel target in Hypertension and associated comorbidities – NGAL-HT

The scientific approach was to use genetic rodent models to access the role of NGAL in various disease processes such as hypertension, mineralocorticoid receptor hyperactivation, chronic kidney diseases.

we identified for the first time a direct role of NGAL in blood pressure via the control of renal Na balance (Bonnard et al. Hypertension 2023). We identified a novel Ngal-mediated signaling pathway modulating the NCC transporter and identified a novel regulatory mechanism of NCC (Bonnard et al. Hypertension 2023). We showed, for the first time, a correlation between plasma NGAL and renal Na transport in the Stanislas cohort. We demonstrated the usefulness of the NGAL inhibitors we previously developed (and patented), especially the GP1 compound. We demonstrated that the pharmacological inhibition of NGAL phenocopy the NGAL gene inactivation in mice on salt-sensitive blood pressure.

The results have opened up new scientific avenues, leading to both ongoing and groundbreaking projects, for example, those concerning heart valves funded by the French National Research Agency (ANR MIRAVALVE) or the French Federation of Cardiology, or chronic inflammatory bowel diseases (in collaboration, as an ANR MYRIAD partner), or certain ocular pathologies (to explore the role of NGAL, for example).

The NGAL-HT project will increase knowledge on pathophysiological mechanisms but also provide new insights in genetic aspects of blood pressure and proof of concept studies for use of NGAL as a novel therapeutic target in the field.

Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects. Barrera-Chimal J, Lima-Posada I, Bakris GL, Jaisser F. Nat Rev Nephrol. 2021 in press
Roles of Mineralocorticoid Receptors in Cardiovascular and Cardiorenal Diseases. Jonatan Barrera-Chimal, Benjamin Bonnard and Frederic Jaisser. Annual Rev Physiol, 2022 in press

brevet déposé: 1. NGAL inhibitors: PCT/EP2020/056077, filled March 6, 2020; USA 17/434,535 filed August 27, 2021

Our recent exploratory studies identified novel key roles of NGAL (Neutrophil Gelatinase-Associated Lipocalin) in the control of blood pressure. NGAL was previously identified by partners 1 and 2 as a novel mineralocorticoid target leading to experimental and clinical studies, as well as a strong patent portfolio and licensing. This unexpected effect on blood pressure control and its potential therapeutic impact led to the NGAL-HT consortium associating synergic expertise in pathophysiological research, translational studies and population genetics.

Hypothesis: NGAL is involved in blood pressure control via the modulation of renal Na transport. Moreover targeting NGAL may have several beneficial effects in CV and renal comorbidities related to hypertension. Our objectives are to 1) determine the underlying mechanisms, 2) study the correlations between plasma NGAL, NGAL polymorphisms, blood pressure and Na excretion in dedicated human cohorts and 3) study the therapeutic efficacy of new NGAL inhibitors already identified by partners 1-2.

The NGAL-HT project will increase knowledge on pathophysiological mechanisms but also provide new insights in genetic aspects of blood pressure and proof of concept studies for use of NGAL as a novel therapeutic target in the field.