The Mineralocorticoid Receptor in the Vasculature: Friend or Foe?

Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed, including in vascular endothelial and smooth muscle cells. Ample data demonstrate that endothelial and smooth muscle cell MRs contribute to cardiovascular disease in response to risk factors (aging, obesity, hypertension, atherosclerosis) by inducing vasoconstriction, vascular remodeling, inflammation, and oxidative stress. Extrapolating from its role in disease, evidence supports beneficial roles of vascular MRs in the context of hypotension by promoting inflammation, wound healing, and vasoconstriction to enhance survival from bleeding or sepsis. Advances in understanding how vascular MRs become activated are also reviewed, describing transcriptional, ligand-dependent, and ligand-independent mechanisms. By synthesizing evidence describing how vascular MRs convert cardiovascular risk factors into disease (the vascular MR as a foe), we postulate that the teleological role of the MR is to coordinate responses to hypotension (the MR as a friend).

Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis.

Daily dietary potassium (K+) intake may be as large as the extracellular K+ pool. To avoid acute hyperkalemia, rapid removal of K+ from the extracellular space is essential. This is achieved by translocating K+ into cells and increasing urinary K+ excretion. Emerging data now indicate that the renal thiazide-sensitive NaCl cotransporter (NCC) is critically involved in this homeostatic kaliuretic response. This suggests that the early distal convoluted tubule (DCT) is a K+ sensor that can modify sodium (Na+) delivery to downstream segments to promote or limit K+ secretion. K+ sensing is mediated by the basolateral K+ channels Kir4.1/5.1, a capacity that the DCT likely shares with other nephron segments. Thus, next to K+-induced aldosterone secretion, K+ sensing by renal epithelial cells represents a second feedback mechanism to control K+ balance. NCC's role in K+ homeostasis has both physiological and pathophysiological implications. During hypovolemia, NCC activation by the renin-angiotensin system stimulates Na+ reabsorption while preventing K+ secretion. Conversely, NCC inactivation by high dietary K+ intake maximizes kaliuresis and limits Na+ retention, despite high aldosterone levels. NCC activation by a low-K+ diet contributes to salt-sensitive hypertension. K+-induced natriuresis through NCC offers a novel explanation for the antihypertensive effects of a high-K+ diet. A possible role for K+ in chronic kidney disease is also emerging, as epidemiological data reveal associations between higher urinary K+ excretion and improved renal outcomes. This comprehensive review will embed these novel insights on NCC regulation into existing concepts of K+ homeostasis in health and disease.

Roles of Mineralocorticoid Receptors in Cardiovascular and Cardiorenal Diseases.

Mineralocorticoid receptor (MR) activation in the heart and vessels leads to pathological effects, such as excessive extracellular matrix accumulation, oxidative stress, and sustained inflammation. In these organs, the MR is expressed in cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and inflammatory cells. We review the accumulating experimental and clinical evidence that pharmacological MR antagonism has a positive impact on a battery of cardiac and vascular pathological states, including heart failure, myocardial infarction, arrhythmic diseases, atherosclerosis, vascular stiffness, and cardiac and vascular injury linked to metabolic comorbidities and chronic kidney disease. Moreover, we present perspectives on optimization of the use of MR antagonists in patients more likely to respond to such therapy and review the evidence suggesting that novel nonsteroidal MR antagonists offer an improved safety profile while retaining their cardiovascular protective effects. Finally, we highlight future therapeutic applications of MR antagonists in cardiovascular injury.

Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study.

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.

Relationship Between Renin, Aldosterone, Aldosterone-to-Renin Ratio and Arterial Stiffness and Left Ventricular Mass Index in Young Adults.

BACKGROUND: Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease. METHODS: The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure. RESULTS: This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P<0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P<0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P<0.001) and 27 (21.0 versus 15.6; P<0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (ß=0.009 [95% CI, 0.001-0.017]; P=0.027) and between aldosterone-to-renin ratio and LVMI in females (ß=0.098 [95% CI, 0.001-0.196]; P=0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age. CONCLUSIONS: Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

The metalloproteinase ADAM10 sheds angiotensin-converting enzyme (ACE) from the pulmonary endothelium as a soluble, functionally active convertase.

The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the regulation of blood pressure and fluid balance, with angiotensin-converting enzyme (ACE) being a key transmembrane enzyme that converts angiotensin I to angiotensin II. Hence, ACE activity is an important drug target in cardiovascular pathologies such as hypertension. Our study demonstrates that human pulmonary microvascular endothelial cells (HPMECs) are an important source of proteolytically released ACE. The proteolytic release of transmembrane proteins, a process known as ectodomain shedding, is facilitated by membrane proteases called sheddases. By knockout and inhibition studies, we identified ADAM10 (A disintegrin and metalloprotease 10) as a primary sheddase responsible for ACE release in HEK293 cells. The function of ADAM10 as primary, constitutive sheddase of ACE was confirmed in HPMECs. Moreover, we demonstrated the physiological relevance of ADAM10 for ACE shedding in ex vivo precision cut lung slices (PCLS) from human and mouse lungs. Notably, ADAM17 activity is not directly involved in ACE shedding but indirectly by regulating ACE mRNA and protein levels, leading to increased ADAM10-mediated ACE shedding. Importantly, soluble ACE generated by shedding is enzymatically active and can thereby participate in systemic RAAS functions. Taken together, our findings highlight the critical role of ADAM10 (directly) and ADAM17 (indirectly) in ACE shedding and RAAS modulation.

Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation.

Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca2+ oscillations. We revisit data to understand how a multitude of conductances may underlie voltage/Ca2+ oscillations, recognizing that zG layer self-renewal and cell heterogeneity may complicate this task. We review recent data to understand rosette architecture and apply maxims derived from computational network modeling to understand rosette function. The challenge going forward is to uncover how the rosette orchestrates the behavior of a functional network of conditional oscillators to control zG layer performance and aldosterone secretion.

MicroRNA-19 is regulated by aldosterone in a sex-specific manner to alter kidney sodium transport.

A key regulator of blood pressure homeostasis is the steroid hormone aldosterone, which is released as the final signaling hormone of the renin-angiotensin-aldosterone-signaling (RAAS) system. Aldosterone increases sodium (Na+) reabsorption in the kidney distal nephron to regulate blood volume. Unregulated RAAS signaling can lead to hypertension and cardiovascular disease. The serum and glucocorticoid kinase (SGK1) coordinates much of the Na+ reabsorption in the cortical collecting duct (CCD) tubular epithelial cells. We previously demonstrated that aldosterone alters the expression of microRNAs (miRs) in CCD principal cells. The aldosterone-regulated miRs can modulate Na+ transport and the cellular response to aldosterone signaling. However, the sex-specific regulation of miRs by aldosterone in the kidney distal nephron has not been explored. In this study, we report that miR-19, part of the miR-17-92 cluster, is upregulated in female mouse CCD cells in response to aldosterone activation. Mir-19 binding to the 3'-untranslated region of SGK1 was confirmed using a dual-luciferase reporter assay. Increasing miR-19 expression in CCD cells decreased SGK1 message and protein expression. Removal of this cluster using a nephron-specific, inducible knockout mouse model increased SGK1 expression in female mouse CCD cells. The miR-19-induced decrease in SGK1 protein expression reduced the response to aldosterone stimulation and may account for sex-specific differences in aldosterone signaling. By examining evolution of the miR-17-92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1, first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis.NEW & NOTEWORTHY Expression of the microRNA-17-92 cluster is upregulated by aldosterone in mouse cortical collecting duct principal cells, exclusively in female mice. MiR-19 in this cluster targets the serum and glucocorticoid kinase (SGK1) to downregulate both mRNA and protein expression, resulting in a decrease in sodium transport across epithelial cells of the collecting duct. The miR-17-92 cluster is evolutionarily conserved and may act as a novel feedback regulator for aldosterone signaling in females.

The GLP-1-mediated gut-kidney cross talk in humans: mechanistic insight.

Incretin-based therapy is an antidiabetic and antiobesity approach mimicking glucagon-like peptide-1 (GLP-1) with additional end-organ protection. This review solely focuses on randomized, controlled mechanistic human studies, investigating the renal effects of GLP-1. There is no consensus about the localization of GLP-1 receptors (GLP-1Rs) in human kidneys. Rodent and primate data suggest GLP-1R distribution in smooth muscle cells in the preglomerular vasculature. Native GLP-1 and GLP-1R agonists elicit renal effects. Independently of renal plasma flow and glomerular filtration rate, GLP-1 has a natriuretic effect but only during volume expansion. This is associated with high renal extraction of GLP-1, suppression of angiotensin II, and increased medullary as well as cortical perfusion. These observations may potentially indicate that impaired GLP-1 sensing could establish a connection between salt sensitivity and insulin resistance. It is concluded that a functional GLP-1 kidney axis exists in humans, which may play a role in renoprotection.

Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling.

Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α-subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC ß- and γ-subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+ Cl- cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+ ], but the addition of high salt markedly attenuated the aldosterone-dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC-positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross-sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC-positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+ . KEY POINTS: Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake. Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron. Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit. Aldosterone and its associated decrease in blood [K+ ] lead to an increased expression of Na-Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+ ]. Upstream kinase regulators and tubule remodelling do not explain these results.

Loss of the alpha subunit distal furin cleavage site blunts ENaC activation following Na+ restriction.

Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild-type (WT) and αF2M mice. Patch-clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride-sensitive short-circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single-channel activity was significantly lower in kidney tubules from Na+-restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+-restricted αF2M vs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. KEY POINTS: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole-animal physiology remain to be addressed. We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice). We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction. ENaC function at the organ level was preserved in salt-restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis. These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo.

Commensal microbiota regulate aldosterone.

The gut microbiome regulates many important host physiological processes associated with cardiovascular health and disease; however, the impact of the gut microbiome on aldosterone is unclear. Investigating whether gut microbiota regulate aldosterone can offer novel insights into how the microbiome affects blood pressure. In this study, we aimed to determine whether gut microbiota regulate host aldosterone. We used enzyme-linked immunosorbent assays (ELISAs) to assess plasma aldosterone and plasma renin activity (PRA) in female and male mice in which gut microbiota are intact, suppressed, or absent. In addition, we examined urinary aldosterone. Our findings demonstrated that when the gut microbiota is suppressed following antibiotic treatment, there is an increase in plasma and urinary aldosterone in both female and male mice. In contrast, an increase in PRA is seen only in males. We also found that when gut microbiota are absent (germ-free mice), plasma aldosterone is significantly increased compared with conventional animals (in both females and males), but PRA is not. Understanding how gut microbiota influence aldosterone levels could provide valuable insights into the development and treatment of hypertension and/or primary aldosteronism. This knowledge may open new avenues for therapeutic interventions, such as probiotics or dietary modifications to help regulate blood pressure via microbiota-based changes to aldosterone.NEW & NOTEWORTHY We explore the role of the gut microbiome in regulating aldosterone, a hormone closely linked to blood pressure and cardiovascular disease. Despite the recognized importance of the gut microbiome in host physiology, the relationship with circulating aldosterone remains largely unexplored. We demonstrate that suppression of gut microbiota leads to increased levels of plasma and urinary aldosterone. These findings underscore the potential of the gut microbiota to influence aldosterone regulation, suggesting new possibilities for treating hypertension.

5/6 Nephrectomy Impairs Acute Kaliuretic Responses and Predisposes to Postprandial Hyperkalemia.

The susceptibility of patients with chronic kidney disease (CKD) to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na+) and potassium (K+) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K+ loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this to the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K+ loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K+ concentrations in 5/6Nx rats which were accompanied by corresponding increases in plasma aldosterone. Acute K+ loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase (SPAK) and the sodium-chloride cotransporter (NCC) both in sham and 5/6Nx rats. In contrast, the acute K+ load decreased the Na+/hydrogen exchanger 3 (NHE3) and increased serum- and glucocorticoid-regulated kinase 1 (SGK1) and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K+ load which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia.

Physiologic homeostasis after pig-to-human kidney xenotransplantation.

Demand for kidney grafts outpaces supply, limiting kidney transplantation as a treatment for kidney failure. Xenotransplantation has the potential to make kidney transplantation available to many more patients with kidney failure, but the ability of xenografts to support human physiologic homeostasis has not been established. A brain-dead adult decedent underwent bilateral native nephrectomies followed by 10 gene-edited (four gene knockouts, six human transgenes) pig-to-human xenotransplantation. Physiologic parameters and laboratory values were measured for seven days in a critical care setting. Data collection aimed to assess homeostasis by measuring components of the renin-angiotensin-aldosterone system, parathyroid hormone signaling, glomerular filtration rate, and markers of salt and water balance. Mean arterial blood pressure was maintained above 60 mmHg throughout. Pig kidneys secreted renin (post-operative day three to seven mean and standard deviation: 47.3 ± 9 pg/mL). Aldosterone and angiotensin II levels were present (post-operative day three to seven, 57.0 ± 8 pg/mL and 5.4 ± 4.3 pg/mL, respectively) despite plasma renin activity under 0.6 ng/mL/hr. Parathyroid hormone levels followed ionized calcium. Urine output down trended from 37 L to 6 L per day with 4.5 L of electrolyte free water loss on post-operative day six. Aquaporin 2 channels were detected in the apical surface of principal cells, supporting pig kidney response to human vasopressin. Serum creatinine down trended to 0.9 mg/dL by day seven. Glomerular filtration rate ranged 90-240 mL/min by creatinine clearance and single-dose inulin clearance. Thus, in a human decedent model, xenotransplantation of 10 gene-edited pig kidneys provided physiologic balance for seven days. Hence, our in-human study paves the way for future clinical study of pig-to-human kidney xenotransplantation in living persons.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Decoding the role of aldosterone in glycation-induced diabetic complications.

Diabetes-mediated development of micro and macro-vascular complications is a global concern. One of the factors is hyperglycemia induced the non-enzymatic formation of advanced glycation end products (AGEs). Accumulated AGEs bind with receptor of AGEs (RAGE) causing inflammation, oxidative stress and extracellular matrix proteins (ECM) modifications responsible for fibrosis, cell damage and tissue remodeling. Moreover, during hyperglycemia, aldosterone (Aldo) secretion increases, and its interaction with mineralocorticoid receptor (MR) through genomic and non-genomic pathways leads to inflammation and fibrosis. Extensive research on individual involvement of AGEs-RAGE and Aldo-MR pathways in the development of diabetic nephropathy (DN), cardiovascular diseases (CVDs), and impaired immune system has led to the discovery of therapeutic drugs. Despite mutual repercussions, the cross-talk between AGEs-RAGE and Aldo-MR pathways remains unresolved. Hence, this review focuses on the possible interaction of Aldo and glycation in DN and CVDs, considering the clinical significance of mutual molecular targets.

Pyridoxal-5'-phosphate: A cost-effective treatment candidate for hypertensive patients?

OBJECTIVES: Because angiotensin (Ang) II is an essential vasoconstrictive peptide, we analyzed the impact of its post-translational modification to pyruvamide-Ang II (Ang P) by pyridoxal-5'-phosphate (PLP) on blood pressure. PLP is a less expensive vitamin B6 derivative and, therefore, could be a cost-effective drug against hypertension. METHODS: Effect of Ang P on calcium ion entry into vascular smooth muscle cells (VSMCs) was analyzed. Binding affinity of Ang P to angiotensin II type 1 receptor (AT1R) was measured. Vasoconstrictive effect of Ang P was investigated using the bioassay of isolated perfused rat kidneys. Spontaneously hypertensive rats (SHR) were administered PLP. Additionally, Wistar Kyoto rats (WKY) received Ang II and PLP. Blood pressure was measured time-dependently. RESULTS: Ang II, incubated with PLP, was post-translationally modified to Ang P. Calcium ion entry in VSMCs was significantly lower with Ang P compared to Ang II. Binding affinity of Ang P to AT1R was lower compared to Ang II. Perfusion pressure of isolated perfused rat kidneys increased less by Ang P than by Ang II. Blood pressure of SHR treated with PLP decreased significantly. Blood pressure of WKY rats treated with Ang II was increased to hypertensive values, whereas blood pressure of WKY rats cotreated with Ang II and PLP was not. CONCLUSION: PLP induces a post-translational modification of Ang II decreasing blood pressure in rats. Assuming that increased PLP intake in the form of vitamin B6 might reduce blood pressure in hypertensive patients, PLP might be a cost-effective drug against hypertension.

The angiotensin II receptors type 1 and 2 modulate astrocytes and their crosstalk with microglia and neurons in an in vitro model of ischemic stroke.

BACKGROUND: Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons. RESULT: The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes. CONCLUSION: Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.

Cardiovascular and Renal Treatment in Heart Failure Patients With Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry.

BACKGROUND: Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). METHODS AND RESULTS: This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous 24 months, or estimated glomerular filtration rate < 45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥ 6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1000 patients are presented. CONCLUSIONS: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.

The sympathetic nervous system in heart failure revisited.

Several attempts have been made, by the scientific community, to develop a unifying hypothesis that explains the clinical syndrome of heart failure (HF). The currently widely accepted neurohormonal model has substituted the cardiorenal and the cardiocirculatory models, which focused on salt-water retention and low cardiac output/peripheral vasoconstriction, respectively. According to the neurohormonal model, HF with eccentric left ventricular (LV) hypertrophy (LVH) (systolic HF or HF with reduced LV ejection fraction [LVEF] or HFrEF) develops and progresses because endogenous neurohormonal systems, predominantly the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), exhibit prolonged activation following the initial heart injury exerting deleterious hemodynamic and direct nonhemodynamic cardiovascular effects. However, there is evidence to suggest that SNS overactivity often preexists HF development due to its association with HF risk factors, is also present in HF with preserved LVEF (diastolic HF or HFpEF), and that it is linked to immune/inflammatory factors. Furthermore, SNS activity in HF may be augmented by coexisting noncardiac morbidities and modified by genetic factors and demographics. The purpose of this paper is to provide a contemporary overview of the complex associations between SNS overactivity and the development and progression of HF, summarize the underlying mechanisms, and discuss the clinical implications as they relate to therapeutic interventions mitigating SNS overactivity.