Functional peptides that are derived from natural protein-rich foods possess a wide range of physiological and pharmacological properties and have become ideal alternatives to chemical drugs. In this study, two novel ACE inhibitory peptides, GKGLW (IC50 = 34.96 μM) and GDGLKW (IC50 = 33.98 μM), were screened and identified from soybeans through sequential stepwise double enzymolysis, and their molecular mechanisms were explored by combining computational simulation. Initially, the optimal combination of alkaline protease and chymotrypsin was determined through the analysis of the enzymatic preferences of five different proteases and the ACE inhibitory activity of their hydrolyzed products. Following purification by ultrafiltration and Sephadex G-25 gel chromatography, the amino acid sequences of the peptides were identified by LC-MS/MS and selectively synthesized based on binding energy. Molecular docking and dynamics simulation/generalized born surface area calculation indicated that the peptides mainly interacted with key residues Ala354, Tyr523, and His353 in the ACE active pocket through hydrogen bonds, and hydrophobic and aromatic amino acids were beneficial to the ACE inhibitory activity of the peptides. Additionally, the two peptides showed good stability in simulating the gastrointestinal digestion process. The antihypertensive effects of these two peptides were further verified in a spontaneously hypertensive rats (SHRs) model. In conclusion, this study successfully identified two ACE inhibitory peptides, GKGLW and GDGLKW, from soybeans by combining proteases with different characteristics for stepwise degradation of soy protein, revealing their potential application value as antihypertensive functional foods.

The hormone melatonin (MEL), primarily acknowledged for its role in regulating circadian rhythms, has demonstrated itself to be a complicated molecule with significant implications for vascular physiology. Melatonin exerts extensive physiological effects directly via the MEL receptor type 1 (MT1R) and the MEL receptor type 2 (MT2R), as well as indirectly through the improvement of antioxidant vascular tone.

This review aims to analyse the intricate relationships between MEL and the renin-angiotensin system (RAS) in the vascular attenuation of non-diabetic (non-DM) and diabetic (DM) contexts. Alterations in the expression of RAS components and their dysregulation are prevalent in diabetes. Melatonin exhibits vasoprotective advantages in non-diabetic conditions. In the context of DM, vascular problrms such as vascular endothelial dysfunction (VED), hypertension, and atherosclerosis result from the dysregulation of MEL-RAS interactions. Comprehending the actions of MEL on RAS components in diabetes vasculature is essential for formulating tailored pharmaceutical therapy methods.

This review consolidates existing knowledge regarding the vascular effects of MEL in relation to RAS activation, emphasising its potential role as a modulating factor for angiotensin 1-8 (Ang 1-8), angiotensin-converting enzyme 2 (ACE2), and angiotensin 1-7 (Ang 1-7) in the management of vascular complications associated with DM.

The renin-angiotensin system (RAS) plays a pivotal role in regulating blood volume, systemic vascular resistance, and electrolyte balance, serving as a key component of cardiovascular health. Recent findings highlight the role of angiotensin II (Ang II) in inducing autophagy through angiotensin II receptor type 1 (AT1R). Autophagy, a process of self-degradation and turnover of cellular components, is a homeostatic response that eliminates superfluous materials. Abnormal autophagy promotes cardiomyocyte loss and is critical in hypertrophy and heart failure progression. The RAS's non-canonical axis, which includes the angiotensin 1-9 peptide [Ang-(1-9)], has an anti-hypertrophic effect in cardiomyocytes via an unknown mechanism. In the present study, we aimed to elucidate the effect of Ang-(1-9) on cardiomyocyte autophagy.

We isolated and cultured neonatal ventricular cardiomyocytes and then co-treated them with Ang-(1-9) in the presence of chloroquine (CQ), Ang-II, and chemical inhibitors of different signaling pathways. After treatment, total RNA and protein extracts were obtained to analyze the abundance of different autophagy markers. Likewise, cells were fixed, and autophagy was analyzed through epifluorescence microscopy.

Our findings show that CQ leads to a reduction in autophagy markers, such as microtubule-associated protein 1 light chain 3-II (LC3-II) and total LC3, suggesting Ang-(1-9)'s regulatory role in basal autophagy levels. Furthermore, Ang-(1-9) opposes Ang-II-induced autophagy and induces the phosphorylation of the S234 residue of Beclin-1 (BCN1) via an angiotensin II receptor type 2 (AT2R)/Akt-dependent pathway.

This reduction of Ang-II-induced autophagy by Ang-(1-9) unveils a novel aspect of its action, potentially contributing to its cardioprotective effects.

This study aimed to investigate the role of let-7a-5p in the pathogenesis of essential hypertension (EH) and its correlation with the renin-angiotensin-aldosterone system (RAAS) biomarkers. Ninety-eight EH patients and 24 healthy controls (HC) enrolled in the study were assayed for the relative expression of let-7a-5p in plasma by quantitative real-time polymerase chain reaction (Q-PCR), and biomarkers of the RAAS system, including angiotensin-converting enzyme 2 (ACE2), Ang (1-7), MAS1, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R), were determined by enzyme-linked immunosorbent assay (ELISA) The expression levels of the biomarkers of RAAS system were determined. The results showed that the expression levels of let-7a-5p in the plasma of EH patients were remarkably higher than those of HC. The prediction model of combined let-7a-5p showed high accuracy by constructing a subject operating characteristic (ROC) curve with an area under the curve (AUC) of 0.885, and the reliability of the model was further verified by the Hosmer-Lemeshow (H-L) goodness-of-fit test, the Model Calibration Curve, and the Decision Curve Analysis. Spearman correlation analysis revealed that the expression of let-7a-5p was positively correlated with ACE (r = 0.352, p < 0.001), and mediation analysis indicated that ACE partially mediated between let-7a-5p and the development of hypertension. The present study concludes with the potential of let-7a-5p as a companion diagnostic biomarker for EH. It suggests that there may be a complex regulatory mechanism between it and specific RAAS biomarkers, which provides a new perspective on the pathogenesis and diagnosis of EH.

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

The renin-angiotensin-aldosterone system (RAAS) has a well-established key pathophysiologic role in kidney diseases, and pharmacotherapy targeting this system is a mainstay of treatment of affected human beings, cats, and dogs. Several studies have evaluated the circulating RAAS in animals with spontaneous or experimentally induced kidney diseases. Evidence supporting the activation of this system has been demonstrated in some - but not all - studies and individuals, and the interindividual variability in circulating RAAS markers is high. Advances over the last few decades have expanded our understanding of the system, which now includes the existence of a counterbalancing "alternative" RAAS and tissular renin-angiotensin systems (RASs), the latter regulated independently of the circulating endocrine RAAS. The local RAS in the kidney, termed the intrarenal RAS, is currently recognized as an important regulator of kidney function and mediator of kidney disease. In general, information on the intrarenal RAS is lacking in cats and dogs with kidney diseases; however, existing limited data suggest its activation. Despite the inconsistent evidence for circulating RAAS activation in chronic kidney diseases, RAAS inhibitors have proven effective for the treatment of its common comorbidities, systemic arterial hypertension and renal proteinuria, in both cats and dogs. Further research of the circulating RAAS, the intrarenal RAS, and the interplay between these systems in the context of kidney diseases in companion animals might contribute to the development or refinement of future treatment strategies.

Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B).

To address this, we studied multiple models: in vivo, in a mouse model of ET-1-associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.

Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1-induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)-induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1-induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290-314). Binding sites for MasR on ETBR were identified (amino acids 176-200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)-induced eNOS activity, NO production, and Ang-(1-7)-mediated vasorelaxation, and reduced contractile responses.

We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.

As tissue and intracellular RAS have been reported in different organs and systems. there is local RAS in the ovary, called the ovarian renin-angiotensin system (OVRAS). In this study, we investigated the correlation between RAS (total renin, AngII, Ang1-7), vascular endothelial growth factor (VEGF) and E2 in dominant follicular fluid and ovarian reserve capacity and patient age. Moreover, we analyzed its predictive value for assisted reproductive technology (ART) related outcomes. We observed that the concentrations of VEGF in the follicular fluid of dominant follicles in the ≥ 38 year old group were markedly higher than those in the < 30 year old group (P < 0.05). Total renin and AngII levels were positively correlated with normal fertilization rate (P < 0.05). Ang1-7 levels were positively correlated with the number of mature oocytes, oocyte maturation rate and number of 2PN fertilized cells (P < 0.05). Expressions of VEGF were negatively correlated with number of 2PN fertilized cells, number of D3 embryos for blastocyst culture, number of blastocysts formed, number of available embryos and number of high-quality embryos (P < 0.05). Thus, the expressions of OVRAS (total renin, AngII, Ang1-7 and VEGF) in dominant follicular fluid are correlated with ART outcomes.

Renin-angiotensin-aldosterone system (RAAS) is crucial in cardiovascular homeostasis. Any disruption in this homeostasis often leads to numerous cardiovascular diseases (CVDs) and non-cardiovascular diseases. Small molecules that show ability toward mechanically modulating RAAS components have been developed to address this problem, thus providing opportunities for innovative drug discovery and development. This review is put forth to provide a comprehensive understanding not only on the signaling mechanisms of RAAS that lead to cardiovascular events but also on the use of small molecules targeting the modulation of RAAS components. Further, the detailed descriptions of the drugs affecting the RAAS and their pharmacodynamics, kinetics, and metabolism profiles are provided. This article also covers the limitations of the present therapeutic armory, followed by their mechanistic insights. A brief discussion is offered on the analysis of the chemical space parameters of the drugs affecting RAAS compared to other cardiovascular and renal categories of medications approved by the US FDA. This review provides structural insights and emphasizes the importance of integrating the current therapeutic regimen with pharmacological tactics to accelerate the development of new therapeutics targeting the RAAS components for improved and efficacious cardiovascular outcomes. Finally, chemical spacing parameters of RAAS modulators are provided, which will help in understanding their peculiarities in modulating the RAAS signaling through structural and functional analyses. Furthermore, this review will assist medicinal chemists working in this field in developing better drug regimens with improved selectivity and efficacy.

Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understanding of the intra-ovarian biochemical mechanisms underlying this process in women has lagged compared to our understanding of animal models. This has been largely due to the limited availability of human ovarian samples that can be used to examine changes across the ovulatory period and delineate the underlying cellular/molecular mechanisms in women. Despite this challenge, steady progress has been made to improve our knowledge of the ovulatory process in women by: (i) collecting granulosa cells across the IVF interval, (ii) creating a novel approach to collecting follicular cells and tissues across the periovulatory period from normally cycling women, and (iii) developing unique in vitro models to examine the LH surge or hCG administration-induced ovulatory changes in gene expression, the regulatory mechanisms underlying the ovulatory changes, and the specific functions of the ovulatory factors.

The objective of this review is to summarize findings generated using in vivo and in vitro models of human ovulation, with the goal of providing new insights into the mechanisms underlying the ovulatory process in women.

This review is based on the authors' own studies and a search of the relevant literature on human ovulation to date using PubMed search terms such as 'human ovulation EGF-signaling', 'human ovulation steroidogenesis', 'human ovulation transcription factor', 'human ovulation prostaglandin', 'human ovulation proteinase', 'human ovulation angiogenesis' 'human ovulation chemokine', 'human ovulatory disorder', 'human granulosa cell culture'. Our approach includes comparing the data from the authors' studies with the existing microarray or RNA-seq datasets generated using ovarian cells obtained throughout the ovulatory period from humans, monkeys, and mice.

Current findings from studies using in vivo and in vitro models demonstrate that the LH surge or hCG administration increases the expression of ovulatory mediators, including EGF-like factors, steroids, transcription factors, prostaglandins, proteolytic systems, and other autocrine and paracrine factors, similar to those observed in other animal models such as rodents, ruminants, and monkeys. However, the specific ovulatory factors induced, their expression pattern, and their regulatory mechanisms vary among different species. These species-specific differences stress the necessity of utilizing human samples to delineate the mechanisms underlying the ovulatory process in women.

The data from human ovulation in vivo and in vitro models have begun to fill the gaps in our understanding of the ovulatory process in women. Further efforts are needed to discover novel ovulatory factors. One approach to address these gaps is to improve existing in vitro models to more closely mimic in vivo ovulatory conditions in humans. This is critically important as the knowledge obtained from these human studies can be translated directly to aid in the diagnosis of ovulation-associated pathological conditions, for the development of more effective treatment to help women with anovulatory infertility or, conversely, to better manage ovulation for contraceptive purposes.

N/A.

Prior investigation shows that diabetic patients present hypothalamus-pituitary-adrenal (HPA) axis hyperactivity related to impaired negative feedback. This study investigates the effect of Captopril on the overproduction of adrenocorticotropic hormone (ACTH) and its precursor proopiomelanocortin (POMC) in the pituitary gland of male diabetic mice. Diabetes was induced by intravenous injection of alloxan into fasted Swiss-webster mice, and the animals were treated with Captopril for 14 consecutive days, starting 7 days post-diabetes induction. Plasma corticosterone levels were evaluated by ELISA, while pituitary gland expressions of angiotensin-II type 1 receptor (AT1), angiotensin-II type 2 receptor (AT2), ACTH, Bax, Bcl-2, KI-67, POMC, and glucocorticoid receptor (GR) were evaluated using immunohistochemistry or Western blot. Diabetic mice showed pituitary gland overexpression of AT1, without altering AT2 levels, which were sensitive to Captopril treatment. Furthermore, diabetic mice presented hypercortisolism, along with an increase in the number of corticotroph cells, POMC and ACTH expression, and number of proliferative cells, and a decrease of GR expression in the pituitary gland. In addition, treatment with Captopril reduced systemic corticosterone levels, corticotroph and proliferative cell numbers, and Bcl-2, POMC, and ACTH expression in the pituitary gland of diabetic mice, besides increasing the expression of Bax and GR. In conclusion, these findings show that Captopril is a promising therapy for treating complications associated with HPA axis hyperactivity in diabetic patients, in a mechanism probably related to the downregulation of POMC production in the pituitary gland and subsequent reduction of systemic corticosterone levels.

Prostate cancer is among the most common malignancies found in men, with multifactorial changes occurring altogether to disrupt the pathophysiology of this gland. The Renin-Angiotensin-Aldosterone System (RAAS) is an extensively studied pathway that has newly attributed fundamental roles in cancer biology that impact cell growth, migration, metastasis, and death. These processes are significantly influenced by various components of the RAAS, including prorenin, AT1R, AT2R, and Ang 1-7/Mas receptors. Although the pathophysiology of prostate cancer is complex, targeting the RAAS shows promise as a therapeutic approach. RAAS dysregulation is evident in prostate cancer, and treatments traditionally used for cardiovascular diseases are being explored for cancer therapy. The RAAS pathway has significant effects on the formation of new blood vessels (angiogenesis), the spread of cancer cells to other parts of the body (metastasis), and cell proliferation. In this pathway, angiotensin II and its receptors have crucial functions. Angiotensin II stimulates angiogenesis and cell proliferation through the AT1R, whereas the AT2R has the opposite effect by inhibiting cell growth. Additional pathways involving ACE2/Ang 1-7/Mas also provide potential targets for therapeutic intervention, mitigating the impact of the traditional ACE/Angiotensin II/AT1R pathway. The components of the RAAS influence multiple signalling pathways, such as Androgen Receptor (AR), NF-κB, and PI3K/AKT/mTOR, which enhances our understanding of how it contributes to the progression of prostate cancer. This also provides new possibilities for therapeutic interventions.

The renin-angiotensin system (RAS) is a crucial factor in chronic kidney disease (CKD) progression, affecting renal function and contributing significantly to renal tissue inflammation and fibrosis. Activation of the classical ACE/Ang II/AT1 axis exacerbates renal damage, while the ACE2/Ang-(1-7)/Mas axis has shown promise in reducing CKD progression in numerous animal models. Recently, the ACE2/Ang-(1-7)/Mas axis has emerged as a promising target for CKD interventions. This review provides a comprehensive review of the pivotal role of this axis in CKD pathogenesis and systematically examines various molecules and pharmaceutical agents targeting this pathway. This review aims to elucidate potential strategies for delaying or halting CKD progression, offering patients more effective treatment options.

Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can improve muscle function and exercise capacity, as well as preventing, attenuating or reversing age-related losses in muscle mass, however, the exact mechanisms by which these drugs affect muscle cells, are not yet fully elucidated. Moreover, the potential epigenetic alterations induced in skeletal muscle tissue are also largely unexplored. The aim of this study was to evaluate if enalapril or losartan can change the physical performance and epigenetic profile of skeletal muscle in spontaneously hypertensive rats (SHRs). Male SHRs were treated with water, enalapril (10/mg/kg/day) or losartan (10/mg/kg/day) for 28 consecutive days and submitted to progressive testing on a treadmill. Body weight, perigonadal and retroperitoneal fat, mean arterial pressure, heart rate, running distance and global DNA methylation in the gastrocnemius and soleus muscles were evaluated. Enalapril reduced the rate of weight gain, as well as reducing retroperitoneal fat (p < 0.05) and MAP (p < 0.05) and avoiding the decline in running distance when compared to the other groups (p > 0.05), even 7 days after the end of treatment (p > 0.05). Moreover, enalapril increased global DNA methylation in gastrocnemius muscle cells (p < 0.01). No effects were observed in the losartan-treated group. Our data showed that enalapril prevented the decline in physical function in SHR, as well as reduced the rate of weight gain of the animals. In addition, the results showed, alterations in the global DNA methylation of skeletal muscle cells skeletal structures of the gastrocnemius muscle.

Changes in renal hemodynamics impact renal function during physiological and pathological conditions. In this context, renal vascular resistance (RVR) is regulated by components of the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). However, the interaction between these vasoactive peptides on RVR is still poorly understood. Here, we studied the crosstalk between angiotensin-(1-7) and kinins on RVR. The right kidneys of Wistar rats were isolated and perfused in a closed-circuit system. The perfusion pressure and renal perfusate flow were continuously monitored. Ang-(1-7) (1.0-25.0 nM) caused a sustained, dose-dependent reduction of relative RVR (rRVR). This phenomenon was sensitive to 10 nM A-779, a specific Mas receptor (MasR) antagonist. Bradykinin (BK) promoted a sustained and transient reduction in rRVR at 1.25 nM and 125 nM, respectively. The transient effect was abolished by 4 μM des-Arg9-Leu8-bradykinin (DALBK), a specific kinin B1 receptor (B1R) antagonist. Accordingly, des-Arg9-bradykinin (DABK) 1 μM (a B1R agonist) increased rRVR. Interestingly, pre-perfusion of Ang-(1-7) changed the sustained reduction of rRVR triggered by 1.25 nM BK into a transient effect. On the other hand, pre-perfusion of Ang-(1-7) primed and potentiated the DABK response, this mechanism being sensitive to A-779 and DALBK. Binding studies performed with CHO cells stably transfected with MasR, B1R, and kinin B2 receptor (B2R) showed no direct interaction between Ang-(1-7) with B1R or B2R. In conclusion, our findings suggest that Ang-(1-7) differentially modulates kinin's effect on RVR in isolated rat kidneys. These results help to expand the current knowledge regarding the crosstalk between the RAS and KKS complex network in RVR.

Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin-angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang-(1-7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang-(1-7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang-(1-7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang-(1-7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention.

Leptin has important roles in numerous physiological functions, including those in the regulation of energy balance, and in immune and reproductive systems. However, in the recent years, evidence has implicated it in a number of obesity-related diseases, where its concentrations in serum are significantly elevated. Elevated serum leptin concentrations and increased placental leptin secretion have been reported in women with hypertensive disorders of pregnancy. Whether leptin is responsible for this disorder remains to be established. Leptin injections in healthy rats and mice during pregnancy result in endothelial activation, increased blood pressure and proteinuria. A potential role for leptin in the pathogenesis of pre-eclampsia is hypothesised, particularly in women who are overweight or obese where serum leptin concentrations are often elevated. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy, and hypertensive disorders of pregnancy. In particular, the possible mechanism that may be involved in leptin-induced increase in blood pressure and proteinuria during pregnancy and the potential role of marinobufagenin in this disease entity. We hypothesise a significant role for oxidative stress in this, and propose a conceptual framework on the events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration.

Spermatogenesis is a process that continues until the end of an individual's life, although with reduced activity with advancing age. Inflammation, oxidation, and apoptosis are events considered as predictors of pathogenesis and the development of age-related diseases observed in aged testes. The use of natural compounds with antioxidant and anti-inflammatory properties has a beneficial effect on the inflammatory and oxidative status of the aged testis. The aim of this study was to determine the effect of supplementation with antioxidant-rich black chokeberry (Aronia melanocarpa) juice on several markers of oxidative stress and aging in rat testis. In total, 24 male Wistar rats were divided into three experimental groups: young controls aged 2 months, old controls aged 27 months, and 27-month-old rats supplemented with black chokeberry juice at a dose of 10 mL/kg for 3 months. A. melanocarpa juice supplementation led to reduced oxidative stress, manifested by increased immunoexpression of nNOS, eNOS, and MAS1 in the seminiferous tubules and in the Leydig cells. The morphometrically determined tubule structure data showed no significant differences between the three groups. However, the intensity of the immunoreaction for TRK-C and NT3 in Leydig cells was demonstrably higher in the supplemented old animals compared with the old controls. There was a significantly higher number of blood vessels around the seminiferous tubules in the supplemented animals compared to the old controls. These data indicate that supplementation with A. melanocarpa juice slows down aging processes in the testis and preserves the functional activity of Leydig cells.

Angiotensin-converting enzyme 2 (ACE2) played an important role in the renin-angiotensin-aldosterone system (RAAS) and it was proved to be renoprotective in renal disease. Urinary angiotensin-converting enzyme 2 (uACE2) has been shown to reflect renal injury in human and experimental studies, but its role in feline kidney disease remains unknown.

Our objectives involve comparing uACE2 concentrations and activities in cats across CKD stages with healthy controls, investigating the relationship between uACE2 concentrations, activities, and clinicopathological data in feline CKD patients, and assessing the predictive abilities of both for CKD progression.

A retrospective, case-control study. The concentration and activity of uACE2 were measured by commercial ELISA and fluorometric assay kits, respectively. The concentration was adjusted to give uACE2 concentration-to-creatinine ratios (UACCRs).

In total, 67 cats consisting of 24 control and 43 chronic kidney disease (CKD), including 24 early-stage CKD and 19 late-stage CKD, were enrolled in this study. UACCR values were significantly higher in both early-stage (2.100 [1.142-4.242] x 10-6) and late-stage feline CKD (4.343 [2.992-5.0.71] x 10-6) compared to healthy controls (0.894 [0.610-1.076] x 10-6; p < 0.001), and there was also significant difference between-early stage group and late-stage group (p = 0.026). Urinary ACE2 activity (UAA) was significantly lower in CKD cats (1.338 [0.644-2.755] x pmol/min/ml) compared to the healthy cats (7.989 [3.711-15.903] x pmol/min/ml; p < 0.001). UACCR demonstrated an independent, positive correlation with BUN (p < 0.001), and UAA exhibited an independent, negative correlation with plasma creatinine (p < 0.001). Both UACCR and UAA did not yield significant results in predicting CKD progression based on the ROC curve analysis.

uACE2 concentration and activity exhibit varying changes as renal function declines, particularly in advanced CKD cats.

The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT1 receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT2 receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT2 receptor have opposing effects to the classical AT1 receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.

Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.

Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed.

The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study.

The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 A, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding.

Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

Inflammation triggers a metabolic shift in macrophages from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg effect. This metabolic reprogramming worsens inflammation and cascades into organ damage. Angiotensin-(1-7) [Ang-(1-7)], a small molecule, has demonstrated anti-inflammatory properties. This study investigates whether Ang-(1-7) mitigates inflammation in LPS-induced macrophages and septic mice by regulating the Warburg effect in immune metabolism.

The study induced macrophages with LPS in vitro and measured inflammatory factors using ELISA and Western blot. Key enzymes in glycolysis, mitochondrial respiratory complexes, and citrate pathway key molecules were assessed using Western blot and qRT-PCR. Mitochondrial membrane potential (MMP), lactate, and ATP were measured using assay kits. In vivo, a mouse model of sepsis induced by LPS was used. Kidney tissues were examined for pathological and mitochondrial ultrastructural alterations. The levels of inflammatory factors in mouse serum, glycolysis and citrate pathway-related molecules in the kidney were assessed using qRT-PCR, Western blot, and immunofluorescence techniques. Additionally, MMP, lactate, and ATP in the kidney were measured using assay kits.

In vitro experiments demonstrated that Ang-(1-7) inhibited the levels of inflammatory factors in LPS-treated RAW264.7 cells. It also reduced the expression of key glycolytic enzymes HK2, PFKFB3, and PKM2, as well as lactate levels. Additionally, it decreased intracellular citrate accumulation, enhanced mitochondrial respiratory complexes I and III, and ATP levels. Ang-(1-7) alleviated MMP damage, modulated citrate pathway-related molecules, including SLC25A1, ACLY, and HIF-1α. In vivo experiments showed that Ang-(1-7) lowered glycolysis levels in septic mice, improved mitochondrial ultrastructure and function, mitigated inflammation and renal tissues damage in septic mice, and suppressed the expression of key molecules in the citrate pathway.

In conclusion, Ang-(1-7) can regulate the Warburg effect through the citrate pathway, thereby alleviating inflammation in LPS-induced macrophages and septic mice.

Skeletal muscle possesses regenerative potential via satellite cells, compromised in muscular dystrophies leading to fibrosis and fat infiltration. Angiotensin II (Ang-II) is commonly associated with pathological states. In contrast, Angiotensin (1-7) [Ang-(1-7)] counters Ang-II, acting via the Mas receptor. While Ang-II affects skeletal muscle regeneration, the influence of Ang-(1-7) remains to be elucidated. Therefore, this study aims to investigate the role of Ang-(1-7) in skeletal muscle regeneration. C2C12 cells were differentiated in the absence or presence of 10 nM of Ang-(1-7). The diameter of myotubes and protein levels of myogenin and myosin heavy chain (MHC) were determined. C57BL/6 WT male mice 16-18 weeks old) were randomly assigned to injury-vehicle, injury-Ang-(1-7), and control groups. Ang-(1-7) was administered via osmotic pumps, and muscle injury was induced by injecting barium chloride to assess muscle regeneration through histological analyses. Moreover, embryonic myosin (eMHC) and myogenin protein levels were evaluated. C2C12 myotubes incubated with Ang-(1-7) showed larger diameters than the untreated group and increased myogenin and MHC protein levels during differentiation. Ang-(1-7) administration enhances regeneration by promoting a larger diameter of new muscle fibers. Furthermore, higher numbers of eMHC (+) fibers were observed in the injured-Ang-(1-7), which also had a larger diameter. Moreover, eMHC and myogenin protein levels were elevated, supporting enhanced regeneration due to Ang-(1-7) administration. Ang-(1-7) effectively promotes differentiation in vitroand improves muscle regeneration in the context of injuries, with potential implications for treating muscle-related disorders.

The renin angiotensin system is a key regulator of blood pressure homeostasis. Angiotensin type 1 (AT1R) and 2 receptors (AT2R) have been investigated as targets for cisplatin-induced acute kidney injury; however, their therapeutic potential remains inconclusive. This pilot study aimed to determined the effect that acute cisplatin treatment had on angiotensin II (AngII)-induced contraction in blood vessels and expression profiles of AT1R and AT2R in mouse arteries and kidneys. Male C57BL/6 mice at 18 week of age (n = 8) were treated with vehicle or bolus dose of cisplatin (12.5 mg/kg). Thoracic aorta (TA), adnominal aorta (AA), brachiocephalic arteries (BC), iliac arteries (IL) and kidneys were collected for isometric tension and immunohistochemistry analysis. Cisplatin treatment reduced IL contraction to AngII at all doses (p < 0.01, p < 0.001, p < 0.0001); however, AngII did not induce contraction in TA, AA or BC in either treatment group. Following cisplatin treatment, AT1R expression was significantly upregulated in the media of TA (p < 0.0001) and AA (p < 0.0001), and in the endothelium (p < 0.05) media (p < 0.0001) and adventitia (p < 0.01) of IL. Cisplatin treatment significantly reduced AT2R expression in the endothelium (p < 0.05) and media (p < 0.05) of TA. In renal tubules, both AT1R (p < 0.01) and AT2R (p < 0.05) were increased following cisplatin treatment. Herein, we report that cisplatin reduces AngII-mediated contraction in IL and may be explained by an absence of normal counterregulatory expression of AT1R and AT2R, indicating other factors are involved.

The renin-angiotensin-aldosterone system (RAAS), is an old system with new fundamental roles in cancer biology which influences cell growth, migration, death, and metastasis. RAAS signaling enhances cell proliferation in malignancy directly and indirectly by affecting tumor cells and modulating angiogenesis. Cancer development may be influenced by the balance between the ACE/Ang II/AT1R and the ACE2/Ang 1-7/Mas receptor pathways. The interactions between Ang II/AT1R and Ang I/AT2R as well as Ang1-7/Mas and alamandine/MrgD receptors in the RAAS pathway can significantly impact the development of cancer. Ang I/AT2R, Ang1-7/Mas, and alamandine/MrgD interactions can have anticancer effects while Ang II/AT1R interactions can be involved in the development of cancer. Evidence suggests that inhibitors of the RAAS, which are conventionally used to treat cardiovascular diseases, may be beneficial in cancer therapies.Herein, we aim to provide a thorough description of the elements of RAAS and their molecular play in cancer. Alongside this, the role of RAAS components in sex-dependent cancers as well as GI cancers will be discussed with the hope of enlightening new venues for adjuvant cancer treatment.

Redox imbalance plays essential role in the pathogenesis of cardiovascular diseases. Chronic heart failure (CHF) and hypertension are associated with central oxidative stress, which is partly mediated by the downregulation of antioxidant enzymes in the central autonomic neurons that regulate sympathetic outflow, resulting in sympathoexcitation. Antioxidant proteins are partially regulated by the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2). Downregulation of Nrf2 is key to disrupting central redox homeostasis and mediating sympathetic nerve activity in the setting of Chronic heart failure and hypertension. Nrf2, in turn, is regulated by various mechanisms, such as extracellular vesicle-enriched microRNAs derived from several cell types, including heart and skeletal muscle. In this review, we discuss the role of Nrf2 in regulating oxidative stress in the brain and its impact on sympathoexcitation in Chronic heart failure and hypertension. Importantly, we also discuss interorgan communication via extracellular vesicle pathways that mediate central redox imbalance through Nrf2 signaling.

Coronavirus disease-2019 (COVID-19) is associated with cytokine storm and is characterized by acute respiratory distress syndrome (ARDS) and pneumonia problems. The respiratory system is a place of inappropriate activation of the immune system in people with multiple sclerosis (MS), and this may cause damage to the lung and worsen both MS and infections.The concerns for patients with multiple sclerosis are because of an enhance risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MS patients pose challenges in this pandemic situation, because of the regulatory defect of autoreactivity of the immune system and neurological and respiratory tract symptoms. In this review, we first indicate respiratory issues associated with both diseases. Then, the main mechanisms inducing lung damages and also impairing the respiratory muscles in individuals with both diseases is discussed. At the end, the leading role of physical exercise on mitigating respiratory issues inducing mechanisms is meticulously evaluated.

The renin-angiotensin system activation, partial ischemia/reperfusion (IR) injury, and hypertension contribute to the development of acute kidney injury. The study aims to look at the vascular responses of angiotensin II (Ang II) during Ang II type 1 receptor (AT1R) blockade (losartan) or co-blockades of AT1R and Mas receptor (A779) in two kidneys one clip (2K1C) hypertensive rats which subjected to partial IR injury with and without ischemia preconditioning (IPC).

Thirty-three 2K1C male Wistar rats with systolic blood pressure ≥ 150 mmHg were divided into three groups of sham, IR, and IPC + IR divided into two sub-groups receiving losartan or losartan + A779. The IR group had 45 min partial kidney ischemia, while the IPC + IR group had two 5 min cycles of partial ischemia followed by 10 min of reperfusion and then 45 min of partial kidney ischemia followed by reperfusion. The sham group was subjected to similar surgical procedures except for IR or IPC.

Ang II increased mean arterial pressure in all the groups, but there were no significant differences between the sub-groups. A significant difference was observed in the renal blood flow response to Ang II between two sub-groups of sham and IR groups treated with AT1R blockade alone or co-blockades of AT1R + A779.

These findings demonstrated the significance of AT1R and Mas receptor following partial renal IR in the renal blood flow responses to Ang II in 2K1C hypertensive rats.

Chronic idiopathic intestinal inflammation is an increasing worldwide problem that affects companion animals, especially dogs, and human patients. Although these disease entities have been intensely investigated recently, many questions remain, and alternative therapeutic options are needed. Diarrhea caused by dysregulation of intestinal electrolyte transport and subsequent fluid and electrolyte losses often leads to secondary consequences for the patient. Currently, it is not exactly clear which mechanisms are involved in the dysregulation of intestinal fluid absorption, but differences in intestinal electrolyte shifts between human and canine patients suggest species-specific regulatory or counterregulatory mechanisms. Several intestinal electrolyte transporters are differentially expressed in human patients with inflammatory bowel disease (IBD), whereas there are virtually no studies on electrolyte transporters and their endocrine regulation in canine chronic inflammatory enteropathy. An important mechanism involved in regulating fluid and electrolyte homeostasis is the renin-angiotensin-aldosterone-system (RAAS), which may affect intestinal Na⁺ transport. While RAAS has previously been considered a systemic regulator of blood pressure, additional complex roles of RAAS in inflammatory processes have been unraveled. These alternative RAAS pathways may pose attractive therapeutic targets to address diarrhea and, thus, electrolyte shifts in human IBD and canine chronic inflammatory enteropathy. This article comparatively summarizes the current knowledge about electrolyte transport in human IBD and canine chronic inflammatory enteropathy and the role of RAAS and offers perspectives for novel therapeutic avenues.

Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1-7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1-7)/MAS receptor pathway and resulting in antidepressant-like effects.

Sepsis is a serious syndrome, characterized by the excessive release of inflammatory mediators and thermoregulatory changes, being fever the most common sign. However, despite the importance of Angiotensin (Ang)-(1-7) in controlling the inflammation, the role of the peptide in the febrile response and mortality in animals submitted to experimental model of sepsis is still not clear. In this way, we evaluate the effect of continuous infusion of Ang-(1-7) in inflammatory response, thermoregulation and in mortality of Wistar male rats submitted to colonic ligation puncture (CLP). Before CLP surgery, the infusion pumps (Ang-(1-7), 1.5mg/mL or saline) were inserted into the abdominal cavity and maintained for 24hours. CLP rats showed a febrile response starting from 3h after and persisted until the 24th hour of experiment. Continuous treatment with Ang-(1-7) attenuated the febrile response and reestablished the euthermia 11h after CLP, until the end of experiment, which coincided with an increased heat loss index (HLI). This effect was associated with a decrease in production of pro-inflammatory mediators in liver, white adipose tissue (WAT) and hypothalamus. Moreover, an increase in norepinephrine (NE) content in interscapular brown adipose tissue (iBAT) was observed in CLP animals, which was attenuated with treatment with Ang-(1-7), and decreased mortality in CLP animals treated with Ang-(1-7). Taken together, the present study demonstrates that continuous infusion treatment with Ang-(1-7) can promote a global anti-inflammatory effect, reestablishing the tail skin heat loss as a key thermo-effector function, resulting in an increased survival of animals submitted to experimental sepsis.

The classical view of the renin-angiotensin system (RAS) is that of the circulating hormone pathway involved in salt and water homeostasis and blood pressure regulation. It is also involved in the pathogenesis of cardiac and renal disorders. This led to the creation of drugs blocking the actions of this classical pathway, which improved cardiac and renal outcomes. Our understanding of the RAS has significantly expanded with the discovery of new peptides involved in this complex pathway. Over the last two decades, a counter-regulatory or protective pathway has been discovered that opposes the effects of the classical pathway. Components of RAS are also implicated in the pathogenesis of obesity and its metabolic diseases. The continued discovery of newer molecules also provides novel therapeutic targets to improve disease outcomes. This article aims to provide an overview of an updated understanding of the RAS, its role in physiological and pathological processes, and potential novel therapeutic options from RAS for managing cardiorenal disorders, obesity, and related metabolic disorders.

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H₂S, H₂O₂, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies.

SARS-CoV-2 infection and its clinical manifestations (COVID-19) quickly evolved to a pandemic and a global public health emergency. The limited effectivity of available treatments aimed at reducing virus replication and the lessons learned from other coronavirus infections (SARS-CoV-1 or NL63) that share the internalization process of SARS-CoV-2, led us to revisit the COVID-19 pathogenesis and potential treatments. Virus protein S binds to the angiotensin-converting enzyme 2 (ACE2) initiating the internalization process. Endosome formation removes ACE2 from the cellular membrane preventing its counter-regulative effect mediated by the metabolism of angiotensin II to angiotensin (1-7). Internalized virus-ACE2 complexes have been identified for these coronaviruses. SARS-CoV-2 presents the highest affinity for ACE2 and produces the most severe symptoms. Assuming ACE2 internalization is the trigger for COVID-19 pathogenesis, accumulation of angiotensin II can be viewed as the potential cause of symptoms. Angiotensin II is a strong vasoconstrictor, but has also important roles in hypertrophy, inflammation, remodeling, and apoptosis. Higher levels of ACE2 in the lungs explain the acute respiratory distress syndrome as primary symptoms. Most of the described findings and clinical manifestations of COVID-19, including increased interleukin levels, endothelial inflammation, hypercoagulability, myocarditis, dysgeusia, inflammatory neuropathies, epileptic seizures and memory disorders can be explained by excessive angiotensin II levels. Several meta-analyses have demonstrated that previous use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with better prognosis for COVID-19. Therefore, pragmatic trials to assess the potential therapeutic benefits of renin-angiotensin-aldosterone system inhibitors should be urgently promoted by health authorities to widen the therapeutic options for COVID-19.

Over-activation of the renin-angiotensin-aldosterone system (RAAS) is a leading cause of cardio-renal complications. Oxidative stress is one of the major contributing factors in the over-activation of RAAS. Angiotensin-converting enzyme2/Angiotensin1-7/MasR and natriuretic peptide/particulate guanylyl cyclase receptor-A pathways play a key role in cardiorenal disease protection. Even though individual activation of these pathways possesses cardiorenal protective effects. However, the dual activation of these pathways under stress conditions and the underlying mechanism has not been explored. The study aimed to investigate whether activation of these pathways by dual-acting peptide (DAP) shows a protective effect in-vitro in oxidative stress-induced renal epithelial cells. Oxidative stress was induced in renal epithelial NRK-52E cells with H₂O₂. Co-treatment with Ang 1-7, BNP, and DAP was given for 30 min. AT1, MasR, and pGCA expression were measured by RT-PCR. The markers of oxidative stress and apoptosis were measured by confocal microscopy and FACS analysis. A significant increase in AT1, renin, α-SMA, and NFk-β expression and a significant decrease in MasR and pGCA expression was observed in H₂O₂-induced cells. DAP improved H₂O₂-induced pathological changes in NRK-52E cells. The effect of DAP was superior to that of Ang1-7 and BNP alone. Interestingly, MasR and pGCA inhibitors could block the effect of DAP in H₂O₂-induced cells. DAP shows superior anti-RAAS activity, and it is effective against H₂O₂-induced oxidative stress, apoptosis, fibrosis, and inflammation compared to Ang1-7 and BNP alone. The protective effect is mediated by the dual activation of MasR and pGCA.

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES: • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disorder. Various organ injuries have been reported in response to this virus, including kidney injury and, in particular, kidney tubular injury. It has been discovered that infection with the virus does not only cause new kidney disease but also increases treatment difficulty and mortality rates in people with kidney diseases. In individuals hospitalized with COVID-19, urinary metabolites from several metabolic pathways are used to distinguish between patients with acute kidney injury (AKI) and those without. This review summarizes the pathogenesis, pathophysiology, treatment strategies, and role of metabolomics in relation to AKI in COVID-19 patients. Metabolomics is likely to play a greater role in predicting outcomes for patients with kidney disease and COVID-19 with varying levels of severity in the near future as data on metabolic profiles expand rapidly. Here, we also discuss the correlation between COVID-19 and kidney diseases and the available metabolomics approaches.

In the last 3 years of the pandemic situation, SARS-CoV-2 caused a significant number of deaths. Infection rates for symptomatic and asymptomatic patients are higher than that for death. Eventually, researchers explored that the major deaths are attributed to several comorbidity factors. The confounding factors and gender-associated infection/death rate are observed globally. This suggests that SARS-CoV-2 selects the human system recognizing the internal comorbid environment. This article explored the influences of hypertension, diabetes, cardiovascular, and renovascular disorders in COVID-19 severity and mortality. Brief mechanistic layouts have been presented here, indicating some of the comorbidity as the critical determinant in the COVID-19 pathogenesis and related mortality.

Heart failure (HF) is associated with multiple organ dysfunction and many comorbidities. Its incidence is high among the elderly and is a major health burden worldwide. Cognitive impairment (CI) is highly prevalent in older patients with HF, which is an abnormality in one or more of the items of cognition, attention, memory, language, psychomotor function, and visual spatial acuity. Studies have shown that the incidence of CI in HF patients is between 13 and 54%, and patients with both conditions have poor self-care ability and prognosis, as well as increased mortality rates. However, the mechanisms of CI development in HF patients are still unclear. In this review, we describe the epidemiology and risk factors as well as measures of improving CI in HF patients. We update the latest pathophysiological mechanisms related to the neurocognitive changes in HF patients, expounding on the mechanisms associated with the development of CI in HF patients.

There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC.

Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC.

Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC.

Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.

SARS-CoV-2 is a coronavirus responsible for one of the most serious, modern worldwide pandemics, with lasting and multifaceted effects. By late 2021, SARS-CoV-2 has infected more than 180 million people and has killed more than 3 million. The virus gains entrance to human cells through binding to ACE2 via its surface spike protein and causes a complex disease of the respiratory system, termed COVID-19. Vaccination efforts are being made to hinder the viral spread, and therapeutics are currently under development. Toward this goal, scientific attention is shifting toward variants and SNPs that affect factors of the disease such as susceptibility and severity. This genomic grammar, tightly related to the dark part of our genome, can be explored through the use of modern methods such as natural language processing. We present a semantic analysis of SARS-CoV-2-related publications, which yielded a repertoire of SNPs, genes, and disease ontologies. Population data from the 1000 Genomes Project were subsequently integrated into the pipeline. Data mining approaches of this scale have the potential to elucidate the complex interaction between COVID-19 pathogenesis and host genetic variation; the resulting knowledge can facilitate the management of high-risk groups and aid the efforts toward precision medicine.

The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE^-/-) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE^-/- and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1-7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE^-/- mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE^-/- mice. Vehicle-treated ACE^-/- mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE^-/- mice. Renal Ang(1-7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1-7) concentration in the ACE^-/- mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1-7)/Mas axis, which in turn may deploy its reno-protective effects.

Hypertension, a prevalent chronic ailment, has the potential to impair kidney function, and thereby resulting in hypertensive nephropathy. The escalating incidence of hypertensive nephropathy attributed to the aging population in urban areas, has emerged as a prominent cause of end-stage renal disease. Nevertheless, the intricate pathogenesis of hypertensive nephropathy poses considerable obstacles in terms of precise clinical diagnosis and treatment. This paper aims to consolidate the research findings on the pathogenesis of hypertensive nephropathy by focusing on the perspective of molecular biology.