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Metabolism: Clinical and Experimental Dec 2023Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease.... (Review)
Review
Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or β-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin.
Topics: Male; Humans; Female; Aged; Sarcopenia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Muscle Strength; Human Growth Hormone
PubMed: 37348598
DOI: 10.1016/j.metabol.2023.155597 -
Cell Aug 2023SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B,...
SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.
Topics: Humans; SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2; Receptors, Virus; Virus Internalization; Protein Binding; Membrane Proteins; Nerve Tissue Proteins
PubMed: 37421949
DOI: 10.1016/j.cell.2023.06.005 -
Cells Jul 2023Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to... (Review)
Review
Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin-angiotensin-aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium-glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the "pillars of therapy" such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.
Topics: Humans; Diabetic Nephropathies; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Renin-Angiotensin System; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37566054
DOI: 10.3390/cells12151975 -
Current Hypertension Reports Sep 2023This review describes the discovery and development of ACE inhibitors as antihypertensive agents, compares their efficacy, tolerability, and safety to ARBs, and... (Review)
Review
PURPOSE OF REVIEW
This review describes the discovery and development of ACE inhibitors as antihypertensive agents, compares their efficacy, tolerability, and safety to ARBs, and highlights the contemporary issues surrounding ACE inhibitor use for HTN.
RECENT FINDINGS
Angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed medications for the management of hypertension (HTN) and other chronic conditions including heart failure and chronic kidney disease. These agents inhibit ACE, the enzyme that is responsible for converting angiotensin (AT) I to AT II. Inhibiting the synthesis of AT II causes arterial and venous vasodilation, natriuresis, and a decrease in sympathetic activity, resulting in the reduction of blood pressure. ACE inhibitors are first-line therapy in HTN management along with thiazide diuretics, calcium channel blockers, and angiotensin receptor blockers (ARB). Along with inhibiting AT II synthesis, inhibition of ACE causes accumulation of bradykinin, increasing the risk of bradykinin-mediated side effects like angioedema and cough. Since ARBs do not work on ACE in the renin-angiotensin system, the risk of angioedema and cough are lower with ARBs. Recent evidence has also suggested ARBs may have neuroprotective effects compared to other antihypertensives, including ACE inhibitors; however, this warrants further study. Currently, ACE inhibitors and ARBs have an equal class of recommendation for first-line treatment for the management of HTN. Recent evidence has shown ARBs to be just as effective as ACE inhibitors for HTN but with improved tolerability.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Hypertension; Angiotensin Receptor Antagonists; Cough; Bradykinin; Antihypertensive Agents; Renin-Angiotensin System; Angiotensin II; Angioedema
PubMed: 37284934
DOI: 10.1007/s11906-023-01248-2 -
Kidney International Dec 2023Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this...
Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.
Topics: Humans; Animals; Mice; Diabetic Nephropathies; Lactic Acid; Albuminuria; Angiotensin Receptor Antagonists; Diabetes Mellitus, Type 2; Angiotensin-Converting Enzyme Inhibitors; Kidney; Renal Insufficiency; Protein Isoforms
PubMed: 37843477
DOI: 10.1016/j.kint.2023.08.006 -
Heart Failure Reviews Sep 2023Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials... (Review)
Review
Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.
Topics: Humans; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Heart Failure; Mineralocorticoid Receptor Antagonists; Neprilysin; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 37311917
DOI: 10.1007/s10741-023-10325-2 -
The Surgical Clinics of North America Aug 2023Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the... (Review)
Review
Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.
Topics: Humans; Hypertension, Renovascular; Renin; Angiotensin II; Angiotensin I; Hypertension; Blood Pressure; Sodium
PubMed: 37455034
DOI: 10.1016/j.suc.2023.05.007 -
Hypertension (Dallas, Tex. : 1979) May 2024The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes,... (Review)
Review
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 AT 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 AT 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 AT receptor have opposing effects to the classical AT 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.
Topics: Angiotensin I; Angiotensin II; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Humans
PubMed: 38362781
DOI: 10.1161/HYPERTENSIONAHA.123.21364 -
Renal Failure Dec 2023Data on angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (SV) in patients undergoing maintenance dialysis is scarce. Our study aimed to investigate...
OBJECTIVES
Data on angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (SV) in patients undergoing maintenance dialysis is scarce. Our study aimed to investigate the effect of SV on patients undergoing dialysis.
METHODS
We retrospectively reviewed the data of end-stage kidney disease (ESRD) patients undergoing either peritoneal dialysis (PD) or hemodialysis (HD) in our center. A total of 51 patients receiving SV treatment were enrolled in the SV group. Another 51 age and sex-matched patients on dialysis without SV treatment were selected as the control group. All the patients were regularly followed up in the dialysis clinic. Their clinical, biochemical, and echocardiographic parameters were all recorded at baseline and during follow-up. The effect and safety of SV were further analyzed.
RESULTS
A total of 102 ESRD patients on dialysis (51 patients in the SV group and 51 patients in the control group) were finally enrolled. The median follow-up time was 349 days (interquartile range [IQR]: 217-535 days). The level of B-type natriuretic peptide (BNP) (median [IQR] before and after SV treatment: 596.35 pg/ml [190.6-1714.85] vs. 188.7 pg/ml [83.34-600.35], < 0.001) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) (median [IQR]: 6316.00 pg/ml [4552.00-28598.00] vs. 5074.00 pg/ml [2229.00-9851.00], = 0.022) were significantly decreased after treatment with SV. The variant rate of left ventricular ejection fraction (LVEF) was significantly higher in the SV group compared to the control group, especially in the PD subgroup. No significant difference was found in other echocardiographic parameters between SV and control group. Subgroup analysis of the PD group showed an increase in daily PD ultrafiltration (median [IQR]: 400 ml/d [200-500] vs. 500 ml/d [200-850], = 0.114) after SV treatment. Variant rate of overhydration (OH) measured by the body composition monitor (BCM) of the SV group were significantly different from the control group (median [IQR]: -13.13% [-42.85%-27.84%] vs. 0% [-17.95%-53.85%], = 0.049). The rate of hyperkalemia was slightly higher but without significant difference before and after the introduction of SV (19.6% vs. 27.5%, = 0.350). No event of hypotension and angioedema were observed.
CONCLUSIONS
SV might have a cardio-protective role in ESRD patients undergoing dialysis, especially in PD patients. Serum potassium should be monitored during the treatment.
Topics: Humans; Natriuretic Peptide, Brain; Heart Failure; Stroke Volume; Retrospective Studies; Tetrazoles; Ventricular Function, Left; Renal Dialysis; Valsartan; Drug Combinations; Kidney Failure, Chronic; Angiotensin Receptor Antagonists
PubMed: 37334931
DOI: 10.1080/0886022X.2023.2222841