The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes

Johansen, Marie Louise; Ibarrola, Jaime; Fernández‐Celis, Amaya; Schou, Morten; Sonne, Mette Pauli; Holm, Magnus; Rasmussen, Jeppe Nørgaard; Dela, Flemming; Jaisser, Frédéric; Faber, Jens; Rossignol, Patrick; López‐Andrés, Natalia; Kistorp, Caroline

doi:10.2337/db20-0394

Cited by 8 publications

(3 citation statements)

References 23 publications

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“…In this trial population, spironolactone also reduced circulating markers of fibrosis and blood pressure and improved cardiac structure and function, therefore suggesting a positive benefit–risk ratio 4 . Similar antifibrotic features were also found with high doses (100–200 mg/day) of eplerenone in another trial of patients with type 2 diabetes and a high cardiovascular risk, 17–19 as well as several trials of HF 8 …”

Section: Discussionsupporting

confidence: 70%

Dyskalemia in people at increased risk for heart failure: findings from the heart ‘OMics’ in AGEing (HOMAGE) trial

et al. 2022

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Aims In people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. Methods and resultsThe HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m 2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium < 4.0 mmol/L, 367 had potassium 4.0-5.0 mmol/L, and 58 had potassium > 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium < 3.5 mmol/L was observed in 6 (1.2%) and <4.0 mmol/L in 46 (9%) participants, while a potassium > 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile 25À75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at <4.0 and >5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration < 4.0 mmol/L was positively associated with the use of thiazides (OR: 2.39 [95% CI 1.32; 4.34]), blood urea concentration (OR: 2.15 [95% CI 1.34; 3.39] per 10 mg/dL), and history of hypertension (OR: 2.32 [95% CI 1.02; 5.29]) and negatively associated with randomization to spironolactone (OR: 0.30 [95% CI 0.18; 0.52]). Conclusions In people at risk for developing HF and with relatively normal renal function, spironolactone reduced the risk of hypokalaemia and, at the doses used, was not associated with the occurrence of clinically meaningful hyperkalaemia.

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Section: Discussionsupporting

confidence: 70%

Dyskalemia in people at increased risk for heart failure: findings from the heart ‘OMics’ in AGEing (HOMAGE) trial

et al. 2022

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“…We measured the gene expression of both lipocalin 2 ( Lcn2 ), an MR target we previously identified in the cardiovascular system [ 29 ], and prostaglandin D2 synthase ( Ptgds ), that we identified as a novel MR target specific to the AT in mice and also—importantly—in obese patients [ 9 ]. These targets were recently shown to be modulated by MR in the AT of obese patients treated with eplerenone [ 30 ]. Gene expression of these two genes was induced in the epididymal visceral AT (EVAT) of Adipo-MROE mice, indicating that MR overexpression in adipocytes is associated with MR overactivation, as shown in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

Lefranc

Friederich‐Persson

Foufelle

et al. 2021

IJMS

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Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

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“…Improvement in left ventricular hypertrophy and structural remodeling through the use of MRAs has been confirmed in clinical research (Maron and Leopold, 2010;Leung et al, 2013). Johansen et al found that eplerenone suppresses interstitial fibrosis in the subcutaneous adipose tissue of patients with type 2 diabetes (Johansen et al, 2021). Mahajan et al found that eplerenone improved hemodynamic and ventricular dysfunction in streptozotocin (STZ)-isoproterenol-challenged rats (Mahajan et al, 2018).…”

Section: Introductionmentioning

confidence: 93%

Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy

Xie,

Zang,

Yang

et al. 2024

Front. Pharmacol.

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BackgroundThe renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia.MethodsType 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200 mg/kg daily for 4 weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) in vitro for 24 h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT).ResultsCardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy in vivo. High-glucose stimulation promotes CMT in vitro and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFβ1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy in vitro.ConclusionOur findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-β1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.

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The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes

Cited by 8 publications

References 23 publications

Dyskalemia in people at increased risk for heart failure: findings from the heart ‘OMics’ in AGEing (HOMAGE) trial

Dyskalemia in people at increased risk for heart failure: findings from the heart ‘OMics’ in AGEing (HOMAGE) trial

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

Combination of ADAM17 knockdown with eplerenone is more effective than single therapy in ameliorating diabetic cardiomyopathy

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