Benefit of Mineralocorticoid Receptor Antagonism in renal injury: underlying mechanisms and therapeutic implications – RENOMIR
Renal diseases are a worldwide health problem: more than 500 millions of people in the world (2-3 millions in France) have some degree of kidney damage. Many may evolve into more advanced stages. The cost of renal diseases is a burden to the economy, as population is ageing, and diabetes and high blood pressure, the most frequent causes of renal damage, are increasing. Acute kidney injury (AKI) occurs in approximately 15% of hospitalized patients and up to 40-60% of intensive care unit patients; it appears now as risk factor for developing chronic kidney disease and, particularly, for promoting the transition of chronic kidney disease (CKD) to end-stage renal disease (ESRD). In developing countries many patients cannot be treated either with dialysis or renal transplantation due to cost, availability of kidney transplant or health structures. Therefore, preventing or treating early stages of renal diseases on one hand and decreasing graft dysfunction on the other hand are major challenges in the field.
The benefit of the Mineralocorticoid Receptor (MR) blockade is now demonstrated, based on evidence of its capacity to limit the morbidity and mortality in cardiovascular diseases (cardiac failure, post-infarctus), and possibly in other end-stage organ failure.
The aim of this project is to study the underlying mechanisms and the therapeutical potential of MR antagonism in preventing the decrease of renal function associated with ischemia-reperfusion. Preliminary data from the all the Partners indicate that pharmacological blockade of MR is beneficial to prevent renal damage, especially when alteration in renal hemodynamics is involved.
Working hypothesis: Since the Aldosterone/MR pathway activation participates to the control of vascular function and inflammation, we propose as working hypothesis that part of the effects of MR antagonists (MRA) in IR injury (IRI) is related to the inhibition of vascular MR. Moreover since inflammation is secondarily induced by acute renal ischemia, we will assess whether MR in macrophages is involved in the chronic consequences of acute kidney injury.
To this purpose, we wish to combine 1) pharmacological studies using MRA, 2) experimental approaches on mice with altered levels of MR in the vascular endothelium, in the smooth muscle or in macrophages submitted to renal injury, 3) studies in a large animal porcine model of warm and cold ischemia. This step is a prerequisite to evidence-based evaluation of the potential benefits of MRA in related contexts in patients. Improvement of renal outcome should then be easily translated into human pathology trials. The added value of this project is the effort to link fundamental research approaches to pre-clinical proof of concept to yield novel therapeutic outcomes in nephrology. It will provide new mechanistic insights into the effects of MR activation in renal diseases as well as on the beneficial effects of MRA in these clinical settings.
Monsieur Frederic JAISSER (Institut National de la Santé et de la Recherche Médical)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Institut National de la Santé et de la Recherche Médicale
UNAM Université Autonome du Mexique
INSERM Institut National de la Santé et de la Recherche Médical
Help of the ANR 511,432 euros
Beginning and duration of the scientific project: September 2016 - 36 Months