Finerenone Reduces Intrinsic Arterial Stiffness in Munich Wistar Frömter Rats, a Genetic Model of Chronic Kidney Disease

Gil‐Ortega, Marta; Vega-Martín, Elena; Martín-Ramos, Miriam; González-Blázquez, Raquel; Pulido-Olmo, Helena; Ruiz‐Hurtado, Gema; Schulz, Angela; Ruilope, Luis; Kolkhof, Peter; Somoza, Beatriz; Kreutz, Reinhold; Fernández-Alfonso, Marı́a S.

doi:10.1159/000506275

Cited by 32 publications

(21 citation statements)

References 68 publications

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“…Thus, MR inhibition can prevent the progression of AKI to CKD by reducing inflammation and oxidative stress. Finerenone treatment decreased blood pressure and urinary albumin excretion in a genetic CKD model in rodents (Gil‐Ortega et al, 2020). In the NZB mice model of lupus nephritis, spironolactone decreased proteinuria development (Monrad et al, 2008).…”

Section: Mr Antagonist In Chronic Kidney Diseasementioning

confidence: 99%

Role of mineralocorticoid receptor antagonists in kidney diseases

Patel

Joharapurkar

Jain

2020

Drug Development Research

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Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and eplerenone, are in clinical use to treat hypertension. Increasing evidence suggests that mineralocorticoid receptor activation causes the pathogenesis and progression of chronic kidney disease. Aldosterone‐induced MR activation increases inflammation, fibrosis, and oxidative stress in the kidney. MR antagonists (MRAs) have demonstrated therapeutic actions in chronic kidney disease (CKD), diabetic nephropathy (DN), renal fibrosis, and drug‐induced renal injury in preclinical and clinical studies. We have summarized and discussed these studies in this review. The nonsteroidal MRA, esaxerenone, recently received approval for the treatment of hypertension. It has also shown a positive therapeutic effect in phase 3 clinical trials in patients with DN. Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091 are in different clinical trials in patients with hypertension suffering from renal or hepatic fibrotic diseases. Hyperkalemia associated with MRA therapy has frequently led to the discontinuation of the treatment. The new generation nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum therapeutic benefit for patients suffering from kidney diseases.

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Section: Mr Antagonist In Chronic Kidney Diseasementioning

confidence: 99%

Role of mineralocorticoid receptor antagonists in kidney diseases

Patel

Joharapurkar

Jain

2020

Drug Development Research

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“…Finerenone prevented the coronary endothelial dysfunction evidenced in OVX mice. Recently, a 4 week finerenone treatment has been shown to improve NO bioavailability in aortic rings and in mesenteric arteries from the Munich Wistar Frömter (MWF) rat model of chronic kidney disease 30,31 . Borgo 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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“…A corresponding reduction in albuminuria was also observed [ 81 ]. In the same model, finerenone treatment also dampened plasma matrix metalloproteinase-2 (MMP-2) and MMP-9 activities, lowering arterial stiffness and oxidative stress [ 52 ] ( Table 1 ).…”

Section: The Effects Of Finerenone’s Mechanism Of Actionmentioning

confidence: 99%

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

Kolkhof

Lawatscheck

Filippatos

et al. 2022

IJMS

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Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor.

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Finerenone Reduces Intrinsic Arterial Stiffness in Munich Wistar Frömter Rats, a Genetic Model of Chronic Kidney Disease

Cited by 32 publications

References 68 publications

Role of mineralocorticoid receptor antagonists in kidney diseases

Role of mineralocorticoid receptor antagonists in kidney diseases

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

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

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