Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

Clarisse, Dorien; Deng, Lisa; Bosscher, Karolien De; Lother, Achim

doi:10.1111/bph.15719

Cited by 19 publications

(21 citation statements)

References 139 publications

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“…Another explanation for the absence of the cardiac RORγt-positive γδ T-cell regulation by FIN despite cardioprotective actions could be a different MR/FIN target cell. Tissue- and cell-specific actions of aldosterone, the MR, and MRAs are well known and have been described in different preclinical models [39]. Tissue and cell specificity is likely based on MRs mode of action involving cytoplasmic signaling, cytoplasmic-nuclear translocation, coregulator recruitment, dimerization, and epigenetic processes [39].…”

Section: Discussionmentioning

confidence: 99%

“…Tissue- and cell-specific actions of aldosterone, the MR, and MRAs are well known and have been described in different preclinical models [39]. Tissue and cell specificity is likely based on MRs mode of action involving cytoplasmic signaling, cytoplasmic-nuclear translocation, coregulator recruitment, dimerization, and epigenetic processes [39]. For instance, these components are differentially expressed in epithelial and nonepithelial cells, which subsequently results in different pharmacological effects of MRAs in these cells [39].…”

Section: Discussionmentioning

confidence: 99%

“…Tissue and cell specificity is likely based on MRs mode of action involving cytoplasmic signaling, cytoplasmic-nuclear translocation, coregulator recruitment, dimerization, and epigenetic processes [39]. For instance, these components are differentially expressed in epithelial and nonepithelial cells, which subsequently results in different pharmacological effects of MRAs in these cells [39]. These complex processes could also explain the varying actions of MRAs on different immunomodulatory cell populations and nonimmunological cells.…”

Section: Discussionmentioning

confidence: 99%

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Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage

et al. 2022

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Introduction: Chronic activation of the mineralocorticoid receptor (MR) leads to pathological processes like inflammation and fibrosis during cardiorenal disease. Modulation of immunological processes in the heart or kidney may serve as a mechanistic and therapeutic interface in cardiorenal pathologies. In this study, we investigated anti-inflammatory/-fibrotic and immunological effects of the selective nonsteroidal MR antagonists finerenone (FIN) in the deoxycorticosterone acetate (DOCA)-salt model. Methods: Male C57BL6/J mice were uninephrectomized and received a DOCA pellet implantation (2.4 mg/day) plus 0.9% NaCl in drinking water (DOCA-salt) or received a sham operation and were orally treated with FIN (10 mg/kg/day) or vehicle in a preventive study design. Five weeks after the procedure, blood pressure (BP), urinary albumin/creatinine ratio (UACR), glomerular and tubulointerstitial damage, echocardiographic cardiac function, as well as cardiac/renal inflammatory cell content by FACS analysis were assessed. Results: BP was significantly reduced by FIN. FACS analysis revealed a notable immune response due to DOCA-salt exposure. Especially, infiltrating renal RORγt γδ-positive T cells were upregulated, which was significantly ameliorated by FIN treatment. This was accompanied by a significant reduction of UACR in FIN-treated mice. In the heart, FIN reduced DOCA-salt-induced cardiac hypertrophy, cardiac fibrosis and led to an improvement of the global longitudinal strain. Cardiac actions of FIN were not associated with a regulation of cardiac RORγt γδ-positive T cells. Discussion/Conclusion: The present study shows cardiac and renal protective effects of FIN in a DOCA-salt model. The cardiorenal protection was accompanied by a reduction of renal RORγt γδ T cells. The observed actions of FIN may provide a potential mechanism of its efficacy recently observed in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage

et al. 2022

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“…Established and emerging indications for mineralocorticoid receptor (MR) antagonists include psychiatric disorders, retinal diseases, liver diseases, cardiovascular diseases, kidney disease, and disorders of the skin (a, * MR antagonists in clinical use). Molecular mechanisms and potential pharmacological targets within the MR signaling pathway (b, modified from Clarisse et al, 2022). HRE, hormone response element…”

Section: Linked Articlesmentioning

confidence: 99%

“…Finerenone, as a proof of principle, modifies MR nuclear shuttling and the recruitment of MR co-regulators (Kintscher et al, 2022). Potential other approaches include drugs with preferential uptake in target cells or organs, local delivery systems, inhibition of MR downstream effector molecules, epigenetic inhibitors, or RNA-based antisense therapies (Clarisse et al, 2022).…”

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confidence: 99%

Emerging fields for therapeutic targeting of the aldosterone–mineralocorticoid receptor signaling pathway

Lother

Jaisser

Wenzel

2022

British J Pharmacology

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Rediscovery of the implication of albuminuria in heart failure: emerging classic index for cardiorenal interaction

Min,

Matsumoto,

Asakura

et al. 2024

ESC Heart Failure

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The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes increasingly evident that guideline‐directed medical therapy cannot be one‐size‐fits‐all across a wide range of ejection fractions (EFs) and various aetiologies. Therefore, classifications solely relying on EF and natriuretic peptide make optimization of treatment challenging, and there is a growing exploration of new indicators that enable efficient risk stratification of HF patients. Particularly when considering HF as a multi‐organ interaction syndrome, the cardiorenal interaction plays a central role in its pathophysiology, and albuminuria has gained great prominence as its biomarker, independent from glomerular filtration rate. Albuminuria has been shown to exhibit a linear correlation with cardiovascular disease and HF prognosis in multiple epidemiological studies, ranging from normal (<30 mg/g) to high levels (>300 mg/g). However, on the other hand, it is only recently that the details of the pathological mechanisms that give rise to albuminuria have begun to be elucidated, including the efficient compaction/tightening of the glomerular basement membrane by podocytes and mesangial cells. Interestingly, renal disease, diabetes, and HF damage these components associated with albuminuria, and experimental models have demonstrated that recently developed HF drugs reduce albuminuria by ameliorating these pathological phenotypes. In this review, facing the rapid expansion of horizons in HF treatment, we aim to clarify the current understanding of the pathophysiology of albuminuria and explore the comprehensive understanding of albuminuria by examining the clinically established evidence to date, the pathophysiological mechanisms leading to its occurrence, and the outcomes of clinical studies utilizing various drug classes committed to specific pathological mechanisms to put albuminuria as a novel axis to depict the pathophysiology of HF.

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Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

Abstract: Kom op tegen Kanker (Stand up to Cancer), the Flemish cancer society (grant number STI.VLK.2018.0019.01, to D.C. and K.D.B.).

Cited by 19 publications

References 139 publications

Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage

Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage

Emerging fields for therapeutic targeting of the aldosterone–mineralocorticoid receptor signaling pathway

Rediscovery of the implication of albuminuria in heart failure: emerging classic index for cardiorenal interaction

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