Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Regulation of distal tubule sodium transport: mechanisms and roles in homeostasis and pathophysiology.

Regulated Na+ transport in the distal nephron is of fundamental importance to fluid and electrolyte homeostasis. Further upstream, Na+ is the principal driver of secondary active transport of numerous organic and inorganic solutes. In the distal nephron, Na+ continues to play a central role in controlling the body levels and concentrations of a more select group of ions, including K+, Ca++, Mg++, Cl-, and HCO3-, as well as water. Also, of paramount importance are transport mechanisms aimed at controlling the total level of Na+ itself in the body, as well as its concentrations in intracellular and extracellular compartments. Over the last several decades, the transporters involved in moving Na+ in the distal nephron, and directly or indirectly coupling its movement to that of other ions have been identified, and their interrelationships brought into focus. Just as importantly, the signaling systems and their components-kinases, ubiquitin ligases, phosphatases, transcription factors, and others-have also been identified and many of their actions elucidated. This review will touch on selected aspects of ion transport regulation, and its impact on fluid and electrolyte homeostasis. A particular focus will be on emerging evidence for site-specific regulation of the epithelial sodium channel (ENaC) and its role in both Na+ and K+ homeostasis. In this context, the critical regulatory roles of aldosterone, the mineralocorticoid receptor (MR), and the kinases SGK1 and mTORC2 will be highlighted. This includes a discussion of the newly established concept that local K+ concentrations are involved in the reciprocal regulation of Na+-Cl- cotransporter (NCC) and ENaC activity to adjust renal K+ secretion to dietary intake.

Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A Review of Evolving Treatment Paradigms.

Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD). Multiple clinical studies have defined the efficacy of MR antagonism in attenuating progressive kidney disease, and the US Food and Drug Administration recently approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone for this indication. In this review, we consider the basic science and clinical applicability of MR antagonism. Because hyperkalemia constitutes a constraint to implementing evidence-based MR blockade, we review MRA-associated hyperkalemia in the context of finerenone and discuss evolving mitigation strategies to enhance the safety and efficacy of this treatment. Although the FIDELIO-DKD and FIGARO-DKD clinical trials focused solely on patients with type 2 diabetes mellitus, we propose that MR activation and the resulting inflammation and fibrosis act as a substantive pathogenetic mediator not only in people with diabetic CKD but also in those with CKD without diabetes. We close by briefly discussing both recently initiated and future clinical trials that focus on extending the attributes of MR antagonism to a wider array of nondiabetic kidney disorders, such as patients with nonalbuminuric CKD.

New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11ß-hydroxysteroid dehydrogenases (11ß-HSDs), including 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and type 2 (11ß-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11ß-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.

Recent Research Advances in Renin-Angiotensin-Aldosterone System Receptors.

PURPOSE OF REVIEW: The renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating blood pressure and body fluid, which contributes to the pathophysiology of hypertension and cardiovascular/renal diseases. However, accumulating evidence has further revealed the complexity of this signal transduction system, including direct interactions with other receptors and proteins. This review focuses on recent research advances in RAAS with an emphasis on its receptors. RECENT FINDINGS: Both systemically and locally produced angiotensin II (Ang II) bind to Ang II type 1 receptor (AT1R) and elicit strong biological functions. Recent studies have shown that Ang II-induced activation of Ang II type 2 receptor (AT2R) elicits the opposite functions to those of AT1R. However, accumulating evidence has now expanded the components of RAAS, including (pro)renin receptor, angiotensin-converting enzyme 2, angiotensin 1-7, and Mas receptor. In addition, the signal transductions of AT1R and AT2R are regulated by not only Ang II but also its receptor-associated proteins such as AT1R-associated protein and AT2R-interacting protein. Recent studies have indicated that inappropriate activation of local mineralocorticoid receptor contributes to cardiovascular and renal tissue injuries through aldosterone-dependent and -independent mechanisms. Since the mechanisms of RAAS signal transduction still remain to be elucidated, further investigations are necessary to explore novel molecular mechanisms of the RAAS, which will provide alternative therapeutic agents other than existing RAAS blockers.

RNA sequencing of kidney distal tubule cells reveals multiple mediators of chronic aldosterone action.

The renal aldosterone-sensitive distal tubule (ASDT) is crucial for sodium reabsorption and blood pressure regulation. The ASDT consists of the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct. Due to difficulties in isolating epithelial cells from the ASDT in large quantities, few transcriptome studies have been performed on this segment. Moreover, no studies exist on isolated DCT2 and CNT cells (excluding intercalated cells), and the role of aldosterone for regulating the transcriptome of these specific cell types is largely unknown. A mouse model expressing eGFP in DCT2/CNT/initial cortical collecting duct (iCCD) principal cells was exploited to facilitate the isolation of these cells in high number and purity. Combined with deep RNA sequencing technology, a comprehensive catalog of chronic aldosterone-regulated transcripts from enriched DCT2/CNT/iCCD principal cells was generated. There were 257 significantly downregulated and 290 upregulated transcripts in response to aldosterone ( P < 0.05). The RNA sequencing confirmed aldosterone regulation of well-described aldosterone targets including Sgk1 and Tsc22d3. Changes in selected transcripts such as S100a1 and Cldn4 were confirmed by RT-qPCR. The RNA sequencing showed downregulation of Nr3c2 encoding the mineralocorticoid receptor (MR), and cell line experiments showed a parallel decrease in MR protein. Furthermore, a large number of transcripts encoding transcription factors were downregulated. An extensive mRNA transcriptome reconstruction of an enriched CNT/iCCD principal cell population was also generated. The results provided a comprehensive database of aldosterone-regulated transcripts in the ASDT, allowing development of novel hypotheses for the action of aldosterone.

Genomic and rapid effects of aldosterone: what we know and do not know thus far.

Aldosterone is the most known mineralocorticoid hormone synthesized by the adrenal cortex. The genomic pathway displayed by aldosterone is attributed to the mineralocorticoid receptor (MR) signaling. Even though the rapid effects displayed by aldosterone are long known, our knowledge regarding the receptor responsible for such event is still poor. It is intense that the debate whether the MR or another receptor-the "unknown receptor"-is the receptor responsible for the rapid effects of aldosterone. Recently, G protein-coupled estrogen receptor-1 (GPER-1) was elegantly shown to mediate some aldosterone-induced rapid effects in several tissues, a fact that strongly places GPER-1 as the unknown receptor. It has also been suggested that angiotensin receptor type 1 (AT1) also participates in the aldosterone-induced rapid effects. Despite this open question, the relevance of the beneficial effects of aldosterone is clear in the kidneys, colon, and CNS as aldosterone controls the important water reabsorption process; on the other hand, detrimental effects displayed by aldosterone have been reported in the cardiovascular system and in the kidneys. In this line, the MR antagonists are well-known drugs that display beneficial effects in patients with heart failure and hypertension; it has been proposed that MR antagonists could also play an important role in vascular disease, obesity, obesity-related hypertension, and metabolic syndrome. Taken altogether, our goal here was to (1) bring a historical perspective of both genomic and rapid effects of aldosterone in several tissues, and the receptors and signaling pathways involved in such processes; and (2) critically address the controversial points within the literature as regarding which receptor participates in the rapid pathway display by aldosterone.

Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction.

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.

[Effect of wheat-grain moxibustion on the expression of 5-HT and cortisol in the serum, and MR and GR in the hippocampus in rats with hypothyroidism complicated with depression].

OBJECTIVE: To observe the effect of wheat-grain moxibustion on behavior, 5-hydroxytryptamine (5-HT) and cortisol in the serum, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the hippocampus in rats with hypothyroidism complicated with depression, and to explore the possible mechanism of wheat-grain moxibustion on improving depression in rats with hypothyroidism. METHODS: A total of 32 SPF SD rats were randomly divided into a blank group, a model group, a medication group and a wheat-grain moxibustion group, 8 rats in each group. Except for the blank group, the rats in the remaining groups were treated with intragastric administration of 0.1% propylthiouracil (PTU) suspension at 1 mL/100 g, once a day for 4 weeks to establish the rat model of hypothyroidism, and whether the rats were accompanied with depression-like behavior determined through behavioristics evaluation. The rats in the medication group were intervened with euthyrox at 0.9 mL/100 g, once a day, for 4 weeks; the rats in the wheat-grain moxibustion group were treated with wheat-grain moxibustion at "Dazhui" (GV 14), "Mingmen" (GV 4), "Shenshu" (BL 23) and "Pishu" (BL 20), 7 cones each acupoint, once a day, six times a week for 4 weeks. After the intervention, the depression status was observed by behavioristics test; the contents of thyroid stimulating hormone (TSH), total thyroxine (TT4), 5-HT and cortisol in the serum were detected by ELISA; the protein expressions of MR and GR in hippocampus were detected by Western blot; the expressions of MR mRNA and GR mRNA in the hippocampus were detected by real-time PCR. RESULTS: Before the intervention, compared with the blank group, the scores of open field test (OFT) were decreased and the immobility time of tail suspension test (TST) was prolonged (P<0.05); the serum TSH contents were increased and TT4 contents were decreased (P<0.01) in the other three groups. After the intervention, compared with the model group, the vertical score of OFT was increased and the immobility time of forced swimming test (FST) was prolonged in the medication group (P<0.05), while the scores of three items of OFT were increased (P<0.05, P<0.01), and the immobility time of FST and TST was shortened in the wheat-grain moxibustion group (P<0.01, P<0.05). Compared with the medication group, the immobility time of TST and FST in the wheat-grain moxibustion group was shorter (P<0.05, P<0.01). Compared with the blank group, in the model group, the contents of serum TSH and cortisol were increased (P<0.01, P<0.001), while the contents of serum TT4 and 5-HT were decreased (P<0.01, P<0.001). Compared with the model group, the contents of serum TT4 and 5-HT were increased, while the contents of serum TSH and cortisol were decreased in the medication group and wheat-grain moxibustion group (P<0.01, P<0.05). Compared with the blank group, the protein and mRNA expression of MR, GR in the hippocampus in the model group was decreased (P<0.01, P<0.05, P<0.001); compared with the model group, the protein and mRNA expression of MR in the hippocampus in the medication group were increased (P<0.05), and the protein expression of MR, GR and mRNA expression of MR in the hippocampus in the wheat-grain moxibustion group were increased (P<0.05, P<0.01). Compared with the medication group, the expression of MR mRNA in the wheat-grain moxibustion group was increased (P<0.05). CONCLUSION: Wheat-grain moxibustion could significantly improve thyroid function and depression in rats with hypothyroidism. Its mechanism may be related to up-regulating the protein and mRNA expression of MR and GR in the hippocampus, and then affecting the expression of serum cortisol and 5-HT.

Differential Diagnosis of Major Depressive Disorder and Bipolar Disorder: Genetic and Hormonal Assessment and the Influence of Early-Life Stress.

Few studies have assessed biomarkers for the differentiation of major depressive disorder (MDD) and bipolar disorder (BD). However, some elements of depression such as hormones and receptors of the renin-angiotensin-adrenal system (RAAS), the hypothalamus-pituitary-adrenal (HPA) axis, and history of early-life stress (ELS) could be considered for differential diagnosis. Therefore, this study aimed to assess aldosterone and cortisol levels, MR and GR gene polymorphisms, and ELS as potential biomarkers for differentiating MDD and BD. This study presents a case-control design. Groups comprised samples for genetic, cortisol, and aldosterone analysis: healthy control (HC; n = 113/97/103), MDD (n = 78/69/67) and BD (n = 82/68/65) subjects. Furthermore, all subjects were assessed for diagnostic screening, the severity of depression, and history of ELS by applying MINI-PLUS, GRID-HDRS, and CTQ, respectively. In addition, genotype and allelic frequencies of GR (N363S, R22/23K and BclI) and MR (MI180V and -2G/C) polymorphisms were evaluated via PCR. Our findings demonstrate that basal aldosterone levels may be a biomarker for differentiating BD and MDD. Furthermore, ELS affects the HPA axis in BD, cortisol may be considered a biomarker for distinguishing BD and MDD, but only in the absence of ELS, and, finally, history of ELS and MR-2G/C variant alleles are factors that contribute to the severity of depressive symptoms in MDD and BD.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment.

Real-World Effectiveness of Mineralocorticoid Receptor Antagonists in Primary Aldosteronism.

Objective: To investigate how often target renin is pursued and achieved in patients with primary aldosteronism (PA) and other low renin hypertension (LRH) treated with mineralocorticoid receptor antagonists (MRAs), as reversal of renin suppression was shown to circumvent the enhanced cardiovascular and renal morbidity and mortality in these patients. Patients and Methods: We conducted a retrospective cohort study of patients with PA and LRH treated with MRAs in an academic outpatient practice from January 1, 2000, through May 31, 2020. Results: Of 30,777 patients with hypertension treated with MRAs, only 7.3% were evaluated for PA. 163 patients (123 with PA) had renin followed after MRA initiation. After a median follow-up of 124 [interquartile range, 65-335] days, 70 patients (43%) no longer had renin suppression at the last visit. The proportion of those who achieved target renin was higher in LRH than in PA (53% vs. 40%). Lower baseline serum potassium, lower MRA doses, and beta-blocker use were independently associated with lower odds of achieving target renin in PA, while male sex was associated with target renin in LRH. Overall, 50 patients (30.7%) had 55 adverse events, all from spironolactone, and 26 patients (52%) were switched to eplerenone or had a spironolactone dose reduction. Conclusion: Despite evidence that reversal of renin suppression confers cardio-renal protection in patients with PA and LRH, renin targets are followed in very few and are achieved in under half of such patients seen in an academic setting, with possibly even lower rates in community practices.

The Role of Stress and Mineralocorticoid Receptor Haplotypes in the Development of Symptoms of Depression and Anxiety During Adolescence.

Adolescence is a critical developmental period characterized by heightened levels of depressive and anxiety symptoms. Experiencing chronic or environmental stress, for example, as a result of traumatic events or insensitive parenting, increases the risk for depression and anxiety. However, not all adolescents develop depressive or anxiety symptoms following environmental stressors, due to differences in stress resilience. One of the factors involved in stress resilience is enhanced functionality of the mineralocorticoid receptor (MR), one of the two brain receptors for the stress hormone cortisol. High levels of MR functionality result in relatively lower rates of depression, particularly in women that experienced stress. However, much less is known about MR functionality in relation to the development of adolescent depression and to other internalizing behavior problems such as anxiety. We therefore examined whether the effects of a functional MR haplotype (i.e., the MR CA haplotype) on the development of depressive and anxiety symptoms are sex-dependent, as well as interact with environmental stressors. In a community sample of adolescents (N = 343, 9 waves between age 13 and 24), environmental stressors were operationalized as parental psychological control and childhood trauma. Results showed a sex-dependent effect of MR CA haplotype on the development of depressive symptoms but not for anxiety symptoms. MR CA haplotypes were protective for girls but not for boys. This study sheds more light on the sex-dependent effects of MR functionality related to the development of depressive and anxiety symptoms during adolescence.

New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure.

Aldosterone is a mineralocorticoid hormone with a well-known effect on the renal tubule leading to water retention and potassium reabsorption. Other major effects of the hormone include the induction of proinflammatory activity that leads to progressive fibrotic damage of the target organs, heart and kidney. Blocking the aldosterone receptor therefore represents an important pharmacological strategy to avoid the clinical conditions deriving from heart failure (CHF) and chronic kidney disease (CKD). However, steroidal mineralocorticoid receptor antagonists (MRA) have a low safety profile, especially in CKD patients due to the high incidence of hyperkalemia. A new generation of nonsteroidal MRA has recently been developed to obtain a selective receptor block avoiding side-effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. This review summarizes the results of published preclinical and clinical studies on the nonsteroidal MRA, apararenone esaxerenone and finerenone. The trials showed a better safety profile with maintained drug efficacy compared with steroidal MRA. For this reason, nonsteroidal MRA represent an interesting new therapeutic approach for the prevention of CHF and CKD progression. Some basic research findings also yielded interesting results in acute clinical settings such as myocardial infarction and acute kidney injury.

Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells.

Aldosterone (Aldo) is involved in various cardiovascular diseases such as hypertension and heart failure. Aldo levels are known to be increased in patients with polycystic ovary syndrome, and expression of the mineralocorticoid receptor (MR) has also been detected in the ovary. However, the effect of Aldo on reproductive function has yet to be elucidated. Here, we examined the effects of Aldo on follicular steroidogenesis using primary culture of rat granulosa cells by focusing on the ovarian bone morphogenetic protein (BMP) system acting as a luteinizing inhibitor. We found that Aldo treatment increased FSH-induced progesterone production in a concentration-responsive manner. Consistent with the effects on steroidogenesis, Aldo increased mRNA levels of progesterogenic factor and enzymes including StAR and P450scc, whereas Aldo failed to change FSH-induced estradiol and cAMP synthesis or P450arom expression by granulosa cells. Progesterone production and StAR expression induced by FSH and Aldo were reversed by co-treatment with spironolactone, suggesting the involvement of geonomic MR action. Aldo treatment attenuated Smad1/5/9 phosphorylation and Id1 transcription induced by BMP-6. Furthermore, Aldo enhanced the expression of inhibitory Smad6 in the presence of BMP-6. In addition, BMP-6 downregulated MR expression, while Aldo modulated the mRNA levels of endogenous BMP-6 and BMP type-II receptors, indicating the existence of a feedback loop between the BMP system and MR in granulosa cells. 　Collectively, the results indicated that Aldo predominantly enhances FSH-induced progesterone production by inhibiting BMP-Smad signaling, suggesting a novel role of Aldo in ovarian steroidogenesis and a functional link between MR and BMP pathways in granulosa cells.

Cardiac Mineralocorticoid Receptor and the Na+/H+ Exchanger: Spilling the Beans.

Current evidence reveals that cardiac mineralocorticoid receptor (MR) activation following myocardial stretch plays an important physiological role in adapting developed force to sudden changes in hemodynamic conditions. Its underlying mechanism involves a previously unknown nongenomic effect of the MR that triggers redox-mediated Na+/H+ exchanger (NHE1) activation, intracellular Na+ accumulation, and a consequent increase in Ca2+ transient amplitude through reverse Na+/Ca2+ exchange. However, clinical evidence assigns a detrimental role to MR activation in the pathogenesis of severe cardiac diseases such as congestive heart failure. This mini review is meant to present and briefly discuss some recent discoveries about locally triggered cardiac MR signals with the objective of shedding some light on its physiological but potentially pathological consequences in the heart.

Recent advances in the management of secondary hypertension: chronic kidney disease.

Hypertension in chronic kidney disease (CKD) is the most commonly observed comorbidity and is a risk factor for end-stage renal disease (ESRD) as well as cardiovascular disease (CVD) and mortality. Therefore, suitable blood pressure (BP) control in CKD patients is very important in preventing both CVD and ESRD. We herein describe the recommendations of target BP and the pharmacological drug options from the evidence-based clinical practice guidelines for CKD in 2018 by the Japanese Society of Nephrology (JSN CKD 2018) and recent advances in the management of hypertension in CKD, including sodium-glucose cotransporter (SGLT) 2 inhibitors, mineralocorticoid receptor blockers, and renal denervation. In particular, SGLT2 inhibitors are a new class of "antihypertensive drugs" that have a homeostatic mechanism that regulates body fluid volume in addition to diuretic action, which may be closely associated with their cardiorenal protective properties.

Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2.

Whole exome sequencing and copy-number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop-gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone-regulated transcription factor that acts in the hypothalamic-pituitary-adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523-531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.

Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease.

Accumulating evidence has indicated the potential contributions of aldosterone and mineralocorticoid receptor (MR) to the pathophysiology of cardiovascular disease (CVD) and chronic kidney disease (CKD). Patients with primary aldosteronism have a higher risk of CVD and CKD than those with essential hypertension. MR is strongly expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, glomerular mesangial cells, podocytes, and proximal tubular cells. In these cardiovascular and renal cells, aldosterone-induced cell injury is prevented by MR blockade. Interestingly, MR antagonists elicit beneficial effects on CVD and CKD in subjects with low or normal plasma aldosterone levels. Recent studies have shown that during development of CVD and CKD, cardiovascular and renal MR is activated by glucocorticoid and ligand-independent mechanisms, such as Rac1 signaling pathways. These data indicate that inappropriate activation of local MR contributes to cardiovascular and renal tissue injury through aldosterone-dependent and -independent mechanisms. In this review, recent findings on the specific role of cardiovascular and renal MR in the pathogenesis of CVD and CKD are summarized.

Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets.

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic ß-cells and improving glucose homeostasis.