T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma

Sun, Xue; Li, Chao; Liu, Yuan; Du, Lin‐Juan; Mi, Zeng; Zheng, Xianqing; Zhang, Wu Chang; Liu, Yan; Zhu, Mingyang; Kong, Deping; Zhou, Li; Lü, Limin; Shen, Zhongliang; Yi, Yi; Du, Liqing; Qin, Mu; Liu, Xu; Hua, Zichun; Sun, Shuyang; Yin, Huiyong; Zhou, Bin; Yu, Ying; Zhang, Zhiyuan; Duan, Sheng‐Zhong

doi:10.1161/circresaha.116.310480

Cited by 94 publications

(73 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…31 Recent studies have shown that MR activation promotes T lymphocyte Th17 polarization and reduced the number of Foxp3 + T regulatory cells, effects that were associated with | 3 of 9 BARRERA-CHIMAL And JAISSER aldosterone-induced cardiac and renal damage. 33 It has also been shown that the MR can interact with nuclear factor of activated T cells (NFAT) and activator-protein-1, thus showing that the MR may be important for T-cell activation. Mice with T cells lacking the MR are protected against hypertension induced by angiotensin II and show decreased vascular and renal damage through a mechanism involving a reduced number of interferon-gamma producing T cells.…”

Section: Mr Activation Modulates the Activation Of T Cells And Macrmentioning

confidence: 99%

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Barrera‐Chimal

Jaisser

2019

Acta Physiologica

View full text Add to dashboard Cite

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.

show abstract

Section: Mr Activation Modulates the Activation Of T Cells And Macrmentioning

confidence: 99%

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Barrera‐Chimal

Jaisser

2019

Acta Physiologica

View full text Add to dashboard Cite

show abstract

“…20 Ventricular weight-to-body weight ratio demonstrated significantly less cardiac hypertrophy in TMRKO mice than in littermate control mice 1 and 6 weeks after AAC (Figure 2A). Hematoxilin and eosin staining of cross sections of left ventricles showed significantly decreased cardiomyocyte size in TMRKO mice after AAC ( Figure 2B; Figure S3A).…”

Section: T-cell Mr Deficiency Attenuates Aac-induced Cardiac Hypertromentioning

confidence: 95%

“…20 Male C57BL6/J mice were purchased from SLAC Laboratory Animal Co. Eplerenone was mixed in regular rodent chow (2 g/kg; SLAC Laboratory Animal Co.) and administrated 3 days before surgeries until the end of experiments to deliver a dosage of ≈200 mg/kg/d. Abdominal aortic constriction (AAC) was performed according to previous report.…”

Section: Animals and Surgeriesmentioning

confidence: 99%

Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation

Sun

et al. 2017

Hypertension

Self Cite

View full text Add to dashboard Cite

Although antagonists of mineralocorticoid receptor (MR) have been widely used to treat heart failure, the underlying mechanisms are incompletely understood. Recent reports show that T cells play important roles in pathologic cardiac hypertrophy and heart failure. However, it is unclear whether and how MR functions in T cells under these pathologic conditions. We found that MR antagonist suppressed abdominal aortic constriction–induced cardiac hypertrophy and decreased the accumulation and activation of CD4 + and CD8 + T cells in mouse heart. T-cell MR knockout mice manifested suppressed cardiac hypertrophy, fibrosis, and dysfunction compared with littermate control mice after abdominal aortic constriction. T-cell MR knockout mice had less cardiac inflammatory response, which was illustrated by decreased accumulation of myeloid cells and reduced expression of inflammatory cytokines. Less amounts and activation of T cells were observed in the heart of T-cell MR knockout mice after abdominal aortic constriction. In vitro studies showed that both MR antagonism and deficiency repressed activation of T cells, whereas MR overexpression elevated activation of T cells. These results demonstrated that MR blockade in T cells protected against abdominal aortic constriction–induced cardiac hypertrophy and dysfunction. Mechanistically, MR directly regulated T-cell activation and modulated cardiac inflammation. Targeting MR in T cells specifically may be a feasible strategy for more effective treatment of pathologic cardiac hypertrophy and heart failure.

show abstract

“…Conversely, treatment with IL-17 blocking antibodies prevented DOCA/salt induced cardiac and renal fibrosis in rats [65]. Recently, it has also been shown that MR may interact with a critical transcription factor in T cells, NFAT1, and activator protein-1 to control interferon gamma in T cells and regulate BP and target organ damage in an AngII-infusion murine model [66]. MRA (mineralocorticoid receptor antagonism) by eplerenone and T cell-specific MR ablation (TMRKO) in mice resulted in reduced abdominal aortic constriction (AAC)-induced cardiac hypertrophy, with reduced measures of cardiac fibrosis (% fibrotic area, βMHC, collagen I/III, connective tissue growth factor, and TGFβ1; Table 1) [67].…”

Section: Role Of the Mr In T Cellsmentioning

confidence: 99%

The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature

et al. 2017

View full text Add to dashboard Cite

Background: The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. Summary: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.

show abstract

T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma

Abstract: MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

Cited by 94 publications

References 48 publications

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Vascular and inflammatory mineralocorticoid receptors in kidney disease

Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation

The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature

Contact Info

Product

Resources

About