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Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183842 | GEO | 2023/11/17

REPOSITORIES: GEO

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Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snATAC-seq]

Project description:Mineralocorticoids play a critical role in maintaining sodium and potassium homeostasis and pathophysiological processes including hypertrophy, inflammation and fibrosis. Mineralocorticoid antagonists (MRAs) have shown to protect from kidney and heart disease, however, their molecular mechanism of action is poorly understood. Here we performed single nuclei and bulk transcriptomics and chromatin accessibility analysis to characterize the mode of kidney protection by steroidal and non-steroidal MRA treatment in a rat model of mineralocorticoid-induced cardiorenal end-organ damage. We define mineralocorticoid sensitive cell types and gene network in the kidney. We show that in diseased kidneys specific proximal tubule cells develop an injured profibrotic phenotype expressing Spp1 and Il34. Nonsteroidal finerenone protects from profibrotic differentiation of proximal tubule cells. Profibrotic gene signature can classify human kidney tissue samples and predict prognosis. Our multi-omics approach elucidates target cell types and potential mechanisms of renal protection by finerenone.

2023-11-17 | GSE183840 | GEO

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snRNA-seq]

2023-11-17 | GSE183839 | GEO

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [bulk RNA-seq]

2023-11-17 | GSE183841 | GEO

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism

Project description:Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism

| PRJNA762078 | ENA

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snATAC-seq]

Project description:Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snATAC-seq]

| PRJNA762175 | ENA

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snRNA-seq]

Project description:Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [snRNA-seq]

| PRJNA762174 | ENA

Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [bulk RNA-seq]

Project description:Single cell transcriptomics and chromatin accessibility profiling elucidate the kidney protective mechanism of mineralocorticoid receptor antagonism [bulk RNA-seq]

| PRJNA762176 | ENA

Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension.

Project description:Mineralocorticoid receptor (MR) activation stimulates systemic vascular and left ventricular remodeling. We hypothesized that MR contributes to pulmonary vascular and right ventricular (RV) remodeling of pulmonary hypertension (PH). We evaluated the efficacy of MR antagonism by spironolactone in two experimental PH models; mouse chronic hypoxia-induced PH (prevention model) and rat monocrotaline-induced PH (prevention and treatment models). Last, the biological function of the MR was analyzed in cultured distal pulmonary artery smooth muscle cells (PASMCs). In hypoxic PH mice, spironolactone attenuated the increase in RV systolic pressure, pulmonary arterial muscularization, and RV fibrosis. In rat monocrotaline-induced PH (prevention arm), spironolactone attenuated pulmonary vascular resistance and pulmonary vascular remodeling. In the established disease (treatment arm), spironolactone decreased RV systolic pressure and pulmonary vascular resistance with no significant effect on histological measures of pulmonary vascular remodeling, or RV fibrosis. Spironolactone decreased RV cardiomyocyte size modestly with no significant effect on RV mass, systemic blood pressure, cardiac output, or body weight, suggesting a predominantly local pulmonary vascular effect. In distal PASMCs, MR was expressed and localized diffusely. Treatment with the MR agonist aldosterone, hypoxia, or platelet-derived growth factor promoted MR translocation to the nucleus, activated MR transcriptional function, and stimulated PASMC proliferation, while spironolactone blocked these effects. In summary, MR is active in distal PASMCs, and its antagonism prevents PASMC proliferation and attenuates experimental PH. These data suggest that MR is involved in the pathogenesis of PH via effects on PASMCs and that MR antagonism may represent a novel therapeutic target for this disease.

| S-EPMC3652061 | biostudies-other

Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction.

Project description:Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.

| S-EPMC4393340 | biostudies-literature

Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.

Project description:Vein graft failure rates resulting from adverse graft remodeling remain high with no effective therapy. The mineralocorticoid receptor (MR) plays a role in pathologic arterial remodeling. We demonstrated recently that the MR is upregulated in venous tissues after grafting and hypothesized that MR inhibition would reduce vein graft remodeling.Reverse transcription polymerase chain reaction and immunoblotting were used to examine the expression of the MR and other components of the renin-angiotensin-aldosterone system in human vein and primary human saphenous vein smooth muscle cells (HSVSMC). Adenoviral reporter gene assays were used to explore MR transcriptional activity in HSVSMC. The effect of MR inhibition on vein graft remodeling in vivo was characterized in a mouse vein graft model.Messenger RNAs encoding the MR, 11-?-hydroxysteroid dehydrogenase 2, angiotensin type 1 receptor, and the angiotensin-converting enzyme are expressed in whole HSVSMC. MR and 11-?-hydroxysteroid dehydrogenase 2 protein expression is confirmed, and MR-dependent transcriptional regulation is demonstrated at physiologic aldosterone concentrations in HSVSMC. Treatment of mice with the MR antagonist spironolactone, at doses that do not lower blood pressure (20 mg/kg per day), reduces maximal vein graft intima-media thickness by 68%, with an associated reduction in graft inflammatory cell infiltration and fibrosis.MR is expressed in human venous tissue and cells and modulates gene expression in HSVSMC in response to physiologic aldosterone concentrations. In vivo, MR inhibition reduces vein graft thickening and inflammation. These preclinical data support the potential to use MR antagonists as novel treatments to preserve vein graft patency.

| S-EPMC3525743 | biostudies-literature

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