Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice

Bonnard, Benjamin; Pieronne-Deperrois, Marie; Djerada, Zoubir; El-Moghrabi, Soumaya; Kolkhof, Peter; Mulder, Paul; Jaisser, Frédéric; Messaoudi, Smail

doi:10.1016/j.yjmcc.2018.06.008

Cited by 35 publications

(19 citation statements)

References 52 publications

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“…102 Similarly, we reported that finerenone prevents cardiac diastolic dysfunction in mice with CKD despite maintained renal dysfunction. 103 In the Zucker rat, a model of metabolic syndrome cardiorenal injury, finerenone reduced cardiac hypertrophy, fibrosis, and dysfunction. 88 Cardiac diastolic dysfunction and vascular injury associated with diet-induced obesity are also prevented by MR inhibition.…”

Section: Preclinical Data: Benefit Of Mr Blockade In Diabetic Nephropmentioning

confidence: 99%

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

Barrera‐Chimal

Girerd

Jaisser

2019

Kidney International

178

127

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Section: Preclinical Data: Benefit Of Mr Blockade In Diabetic Nephropmentioning

confidence: 99%

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

Barrera‐Chimal

Girerd

Jaisser

2019

Kidney International

178

127

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“…65 The action of the MR on eNOS activation may be at least partially mediated by the upregulation of the epithelial Na channel expressed in ECs (EnNaC) upon MR activation. 71 Mineralocorticoid receptor inhibition has shown beneficial effects against kidney injury induced by hypertension in animal models, including the stroke-prone spontaneously hypertensive rat, 72 the radiation injury hypertensive model 73 and spontaneously hypertensive rats. 66 We recently showed that endothelial EnNaC KO ameliorates kidney lesions induced by renal ischaemia and leads to faster recovery of kidney oxygenation.…”

Section: Mrs In Kidney Injurymentioning

confidence: 99%

“…70 The protection conferred by MR antagonism in this model is not limited to the kidney, as finerenone was also able to improve the diastolic dysfunction in mice with CKD induced by subtotal nephrectomy. 71 Mineralocorticoid receptor inhibition has shown beneficial effects against kidney injury induced by hypertension in animal models, including the stroke-prone spontaneously hypertensive rat, 72 the radiation injury hypertensive model 73 and spontaneously hypertensive rats. 74,75 In the aldosteronesalt plus unilateral nephrectomy model, which induces kidney damage and elevated blood pressure, eplerenone attenuates hypertension and reduces albuminuria, kidney fibrosis, glomerular injury and pro-inflammatory gene expression.…”

Section: Mrs In Kidney Injurymentioning

confidence: 99%

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Barrera‐Chimal

Jaisser

2019

Acta Physiologica

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Mineralocorticoid receptor (MR) activation in the kidney can occur outside the aldosterone-sensitive distal nephron in sites including the endothelium, smooth muscle and inflammatory cells. MR activation in these cells has deleterious effects on kidney structure and function by promoting oxidative injury, endothelial dysfunction and stiffness, vascular remodelling and calcification, decreased relaxation and activation of T cells and pro-inflammatory macrophages. Here, we review the data showing the cellular consequences of MR activation in endothelial, smooth muscle and inflammatory cells and how this affects the kidney in pathological situations. The evidence demonstrating a benefit of pharmacological or genetic MR inhibition in various models of kidney disease is also discussed.

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“…Diastolic dysfunction in 8‐month‐old OVX mice occurred without increase in LV interstitial collagen type I and III deposits, suggesting that it mainly depended on cardiomyocyte and on coronary functions, rather than in extracellular matrix stiffening at this age. We previously showed that in mice with subtotal nephrectomy‐induced chronic kidney disease, finerenone treatment increased the phosphorylation of Ca 2+ –calmodulin‐dependent kinase‐II (p‐CaMKII), with subsequent increase in the phosphorylation of the phospholamban at Thr 17 , which allows diminishing its inhibitory effect on the sarcoendoplasmic reticulum Ca 2+ ‐ATPase (SERCA) pump, responsible for Ca 2+ recapture in the sarcoplasm in diastole 27 . In cardiomyocytes isolated from ovariectomized rats, Bupha‐Intr et al .…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice

Pieronne-Deperrois

Gueret

Djerada³

et al. 2021

ESC Heart Failure

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Aims In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders. Methods and results Ovariectomy was performed in 4-month-old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end-diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55 † , **P < 0.01 vs. CTL, † P < 0.05 vs. OVX) and compliance (LV end-diastolic pressure-volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26 † † , ***P < 0.001 vs. CTL, † † P < 0.01 vs. OVX). Acetylcholine-induced endothelial-dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7 † † , **P < 0.01 vs. CTL, † † P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO 2 and VCO 2 , all parameters improved by finerenone. Conclusions Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy-induced LV diastolic dysfunction with preserved ejection fraction.

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Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice

Cited by 35 publications

References 52 publications

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice

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