1
|
Chhabra KH, Shoemaker R, Herath CB, Thomas MC, Filipeanu CM, Lazartigues E. Molecular dissection of the role of ACE2 in glucose homeostasis. Physiol Rev 2025; 105:935-973. [PMID: 39918873 PMCID: PMC12124467 DOI: 10.1152/physrev.00027.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/17/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) was discovered 25 years ago as a negative regulator of the renin-angiotensin system, opposing the effects of angiotensin II. Beyond its well-demonstrated roles in cardiovascular regulation and COVID-19 pathology, ACE2 is involved in a plethora of physiopathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in β-cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia, suggesting that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, whereas at the hepatic level ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli, and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications that are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in a cellular and tissue-specific manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders.
Collapse
Affiliation(s)
- Kavaljit H Chhabra
- Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, Kentucky, United States
| | - Robin Shoemaker
- Department of Pediatrics, University of Kentucky, Lexington, Kentucky, United States
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Merlin C Thomas
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Catalin M Filipeanu
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
| | - Eric Lazartigues
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
- Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, United States
| |
Collapse
|
2
|
Mainkar G, Ghiringhelli M, Zangi L. The Potential of RNA Therapeutics in Treating Cardiovascular Disease. Drugs 2025; 85:659-676. [PMID: 40175855 DOI: 10.1007/s40265-025-02173-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2025] [Indexed: 04/04/2025]
Abstract
Despite significant advances in cardiology over the past few decades, cardiovascular diseases (CVDs) remain the leading cause of global mortality and morbidity. This underscores the need for novel therapeutic interventions that go beyond symptom management to address the underlying causal mechanisms of CVDs. RNA-based therapeutics represent a new class of drugs capable of regulating specific genetic and molecular pathways, positioning them as strong candidates for targeting the root causes of a wide range of diseases. Moreover, owing to the vast diversity in RNA form and function, these molecules can be utilized to induce changes at different levels of gene expression regulation, making them suitable for a broad array of medical applications, even within a single disease context. Several RNA-based therapies are currently being investigated for their potential to address various CVD pathologies. These include treatments aimed at promoting cardiac revascularization and regeneration, preventing cardiomyocyte apoptosis, reducing harmful circulating cholesterols and fats, lowering blood pressure, reversing cardiac fibrosis and remodeling, and correcting the genetic basis of inherited CVDs. In this review, we discuss the current landscape of RNA therapeutics for CVDs, with an emphasis on their classifications, modes of action, advancements in delivery strategies and considerations for their implementation, as well as CVD targets with proven therapeutic potential.
Collapse
Affiliation(s)
- Gayatri Mainkar
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Matteo Ghiringhelli
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lior Zangi
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY, 10029, USA.
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| |
Collapse
|
3
|
Fuchs MA, Wolf M. Clinical evidence for independent regulation of vitamin D by intestinal CYP24A1. Reply. J Clin Invest 2025; 135:e191585. [PMID: 40231465 PMCID: PMC11996860 DOI: 10.1172/jci191585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Affiliation(s)
- Michaela A.A. Fuchs
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
| | - Myles Wolf
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| |
Collapse
|
4
|
Potthoff SA, Quack I, Mori Y, Yang G, Arifaj D, Amin E, Meister J, Meuth SG, Kantauskaite M, Argov D, Alesutan I, Voelkl J, Park JK, Rump LC, Rio M, Loirand G, Linker RA, Stegbauer J. Role of Ciliary Neurotrophic Factor in Angiotensin II-Induced Hypertension. Hypertension 2025; 82:652-664. [PMID: 39851048 DOI: 10.1161/hypertensionaha.124.22845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 01/06/2025] [Indexed: 01/25/2025]
Abstract
BACKGROUND Ciliary neurotrophic factor (CNTF), mainly known for its neuroprotective properties, belongs to the IL-6 (interleukin-6) cytokine family. In contrast to IL-6, the effects of CNTF on the vasculature have not been explored. Here, we examined the role of CNTF in AngII (angiotensin II)-induced hypertension. METHODS Hypertension was chronically induced with AngII (1000 ng/kg per minute, osmotic mini-pumps, 14 days) in CNTF-knockout and wild-type mice (with or without nephrectomy and 1% NaCl drinking water). Blood pressure was measured by tail-cuff and radiotelemetry. Effects of CNTF on vascular function and the JAK2/STAT3 pathway were measured in vivo, in the isolated perfused kidney, and in mouse and human vascular smooth muscle cells. RESULTS At baseline, systolic blood pressure was similar between both groups. During AngII infusion, blood pressure increase was significantly attenuated and hypertensive heart and kidney damage was significantly attenuated in CNTF-knockout compared with wild-type mice. Accordingly, renal pressor response to AngII but not KCl or phenylephrine was significantly decreased in CNTF-knockout compared with wild-type mice. Acute CNTF (5 µmol/L) administration nearly restored the AngII-dependent renal pressor response. Chronic CNTF treatment in CNTF-knockout mice increased blood pressure response to AngII to levels observed in wild-type mice. CNTF augments AngII-induced activation of the JAK2/STAT3 pathway in vitro in vascular smooth muscle cells. The significance of this interaction was shown, as the increase in renal pressor response by CNTF was abolished by JAK2/STAT3 inhibitors. CONCLUSIONS Our results demonstrate a major impact of CNTF on blood pressure regulation by modulating AngII-induced pressor response via a JAK2/STAT3-dependent mechanism and indicate that CNTF is an important regulatory cytokine in hypertension.
Collapse
Affiliation(s)
- Sebastian A Potthoff
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
| | - Ivo Quack
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
| | - Yuri Mori
- Department of Nuclear Medicine, Medical Faculty of Heinrich Heine University, University Hospital Düsseldorf, Germany (Y.M.)
| | - Guang Yang
- Division of Nephrology, Peking University Shenzhen Hospital, China (G.Y.)
| | - Denada Arifaj
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
| | - Ehsan Amin
- Institute of Neural and Sensory Physiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (E.A.)
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (E.A.)
| | - Jaroslawna Meister
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Germany; German Center for Diabetes Research, Germany (J.M.)
| | - Sven G Meuth
- Department of Neurology, Medical Faculty, Heinrich Heine University of Düsseldorf, Germany (S.G.M.)
| | - Marta Kantauskaite
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
| | - Doron Argov
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
| | - Ioana Alesutan
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria (I.A., J.V.)
| | - Jakob Voelkl
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria (I.A., J.V.)
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Germany (J.V.)
- German Centre for Cardiovascular Research, Berlin, Germany (J.V.)
| | - Joon-Keun Park
- Department of Nephrology and Hypertension, Hannover Medical School, Germany (J.-K.P.)
| | - Lars C Rump
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
- Cardiovascular Research Institute Düsseldorf, Medical Faculty, Heinrich Heine University, Germany (L.C.R., J.S.)
| | - Marc Rio
- Nantes Université, Centre Hospitalier Universitaire de Nantes, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, l'institut du thorax, France (M.R., G.L.)
| | - Gervaise Loirand
- Nantes Université, Centre Hospitalier Universitaire de Nantes, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, l'institut du thorax, France (M.R., G.L.)
| | - Ralf A Linker
- Department of Neurology, University of Regensburg, Germany (R.A.L.)
| | - Johannes Stegbauer
- Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (S.A.P., I.Q., D. Arifaj, M.K., D. Argov, L.C.R., J.S.)
- Cardiovascular Research Institute Düsseldorf, Medical Faculty, Heinrich Heine University, Germany (L.C.R., J.S.)
| |
Collapse
|
5
|
Li M, Sorensen M, Johnson MA, Ingram SL, Andresen MC, Habecker BA. Hypertension increases sympathetic neuron activity by enhancing intraganglionic cholinergic collateral connections. J Physiol 2025; 603:2005-2020. [PMID: 39031543 PMCID: PMC11662085 DOI: 10.1113/jp286601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/06/2024] [Indexed: 07/22/2024] Open
Abstract
Autonomic dysregulation, including sympathetic hyperactivity, is a common feature of hypertension (HT) and other cardiovascular diseases. The CNS plays a role in driving chronic sympathetic activation in disease, but several lines of evidence suggest that neuroplasticity in the periphery may also contribute. The potential contribution of postganglionic sympathetic neurons to sustained sympathetic hyperactivity is not well understood. We recently discovered that noradrenergic sympathetic neurons in the stellate ganglion (SG) have excitatory cholinergic collateral connections to other neurons within the ganglion. We hypothesize that remodelling of these neurons and increased cholinergic collateral transmission contributes to sustained sympathetic hyperactivity in cardiovascular diseases, including HT. To test that hypothesis, we examined the activity of sympathetic neurons in isolated SG under control conditions and after 1 week of HT induced by peripheral angiotensin II infusion, using whole-cell patch clamp recordings. Despite the absence of central inputs, we observed elevated spontaneous activity and synaptic transmission in sympathetic SG neurons from hypertensive mice that required generation of action potentials. Genetically disrupting cholinergic transmission in noradrenergic neurons decreased basal neuronal activity and prevented angiotensin II-mediated enhancement of activity. Similar changes in activity, driven by increased collateral transmission, were identified in cardiac projecting neurons and neurons projecting to brown adipose tissue. These changes were not driven by altered A-type K+ currents. This suggests that HT stimulates increased activity throughout the intraganglionic network of collateral connections, contributing to the sustained sympathetic hyperactivity characteristic in cardiovascular disease. KEY POINTS: Sympathetic neurons in ganglia isolated from angiotensin II-treated hypertensive mice are more active than neurons from control mice despite the absence of central activation. The enhanced activity is the result of a ganglionic network of cholinergic collaterals, rather than altered intrinsic excitability. Increased neuronal activity was observed in both cardiac neurons and brown adipose tissue-projecting neurons, which are not involved in cardiovascular homeostasis.
Collapse
Affiliation(s)
- Minghua Li
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, United States of America, 97239
| | - Michelle Sorensen
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, United States of America, 97239
| | - Morgan A. Johnson
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, United States of America, 97239
| | - Susan L. Ingram
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Michael C. Andresen
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, United States of America, 97239
| | - Beth A. Habecker
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, United States of America, 97239
| |
Collapse
|
6
|
Voelker TL, Westhoff M, del Villar SG, Thai PN, Chiamvimonvat N, Nieves-Cintrón M, Dickson EJ, Dixon RE. Phosphoinositide Depletion and Compensatory β-adrenergic Signaling in Angiotensin II-Induced Heart Disease: Protection Through PTEN Inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.23.639781. [PMID: 40060428 PMCID: PMC11888262 DOI: 10.1101/2025.02.23.639781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Contractile dysfunction, hypertrophy, and cell death during heart failure are linked to altered Ca2+ handling, and elevated levels of the hormone angiotensin II (AngII), which signals through Gq-coupled AT1 receptors, initiating hydrolysis of PIP2. Chronic elevation of AngII contributes to cardiac pathology, but the mechanisms linking sustained AngII signaling to heart dysfunction remain incompletely understood. Here, we demonstrate that chronic AngII exposure profoundly disrupts cardiac phosphoinositide homeostasis, triggering a cascade of cellular adaptations that ultimately impair cardiac function. Using in vivo AngII infusion combined with phospholipid mass spectrometry, super-resolution microscopy, and functional analyses, we show that sustained AngII signaling reduces PI(4,5)P2 levels and triggers extensive redistribution of CaV1.2 channels from t-tubules to various endosomal compartments. Despite this t-tubular channel loss, enhanced sympathetic drive maintains calcium currents and transients through increased channel phosphorylation via PKA and CaMKII pathways. However, this compensation proves insufficient as cardiac function progressively declines, marked by pathological hypertrophy, t-tubule disruption, and diastolic dysfunction. Notably, we identify depletion of PI(3,4,5)P3 as a critical mediator of AngII-induced cardiac pathology. While preservation of PI(3,4,5)P3 levels through PTEN inhibition did not prevent cellular remodeling or calcium handling changes, it protected against cardiac dysfunction, suggesting effects primarily through reduction of fibrosis. These findings reveal a complex interplay between phosphoinositide signaling, ion channel trafficking, and sympathetic activation in AngII-induced cardiac pathology. Moreover, they establish maintenance of PI(3,4,5)P3 as a promising therapeutic strategy for hypertensive heart disease and as a potential protective adjunct therapy during clinical AngII administration.
Collapse
Affiliation(s)
- Taylor L. Voelker
- Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA; present address: Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Maartje Westhoff
- Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA
| | - Silvia G. del Villar
- Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA
| | - Phung N. Thai
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; present address: David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | - Nipavan Chiamvimonvat
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA; Dept. of Pharmacology, University of California, Davis, CA, 95616, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA; present address: Department of Basic Medical Sciences and Translational Cardiovascular Research Center, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | | | - Eamonn J. Dickson
- Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA
| | - Rose E. Dixon
- Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA
| |
Collapse
|
7
|
Takenaka T, Kobori H, Kurosaki Y, Ishii N, Inoue T, Miyazaki T, Suzuki H, Hasan A, Nishiyama A, Hayashi M. Klotho supplementation decreases blood pressure and albuminuria in mice with lupus nephritis. Eur J Pharmacol 2025; 988:177229. [PMID: 39725133 DOI: 10.1016/j.ejphar.2024.177229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/13/2024] [Accepted: 12/23/2024] [Indexed: 12/28/2024]
Abstract
Klotho deficiency is prevalent in various chronic kidney diseases. Although klotho is known to bind transforming growth factor β (TGFβ) receptor 1 to antagonize renal fibrosis, TGFβ also maintains regulatory T cells with inducing forkhead box protein P3 (FOXP3). Female New Zealand Black/White F1 (NZBWF1) mice were divided into two groups (n = 10 for each): one group was treated with daily subcutaneous injection of klotho protein (30 μg/kg/day) for 8 weeks, and the other only received vehicle. Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2α excretion, albuminuria, and renal angiotensin II levels (p < 0.05 for all) without affecting the glomerular filtration rate (GFR) in NZBWF1 mice. Klotho protein supplementation reduced the number of cluster of differentiation (CD)4+FOXP3+ T cells (p < 0.05) without altering the anti-DNA antibody levels. Klotho supplementation augmented glomerular cellularity, but decreased glomerular crescent formation and interstitial fibrosis in NZBWF1 mice (p < 0.05). Klotho protein supplementation inactivated renal renin-angiotensin system, ameliorating blood pressure and albuminuria in NZBWF1 mice. Klotho supplementation hampered regulatory T cells without altering autoantibodies, exerting dual effects on glomerular pathology in NZBWF1 mice without changes in GFR.
Collapse
Affiliation(s)
- Tsuneo Takenaka
- International University of Health and Welfare, Tokyo, Japan.
| | - Hiroyuki Kobori
- International University of Health and Welfare, Tokyo, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
8
|
Huang JH, Lourenço BN, Coleman AE. The renin-angiotensin-aldosterone system in kidney diseases of cats and dogs. Vet J 2025; 309:106287. [PMID: 39672318 DOI: 10.1016/j.tvjl.2024.106287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/04/2024] [Accepted: 12/04/2024] [Indexed: 12/15/2024]
Abstract
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.
Collapse
Affiliation(s)
- Jane Hc Huang
- Department of Small Animal Medicine and Surgery, University of Georgia, College of Veterinary Medicine, Athens 30601, USA
| | - Bianca N Lourenço
- Department of Small Animal Medicine and Surgery, University of Georgia, College of Veterinary Medicine, Athens 30601, USA.
| | - Amanda E Coleman
- Department of Small Animal Medicine and Surgery, University of Georgia, College of Veterinary Medicine, Athens 30601, USA
| |
Collapse
|
9
|
Choi HI, Jung IA, Kim SW. Peroxiredoxin 5 Acts as a Negative Regulator of the Sodium-Chloride Cotransporter Involved in Alleviating Angiotensin II-Induced Hypertension. Antioxidants (Basel) 2025; 14:100. [PMID: 39857434 PMCID: PMC11761572 DOI: 10.3390/antiox14010100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/07/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Chronic kidney disease (CKD) and hypertension are interconnected, worsening each other. Recent studies have shown that the reduction of peroxiredoxin 5 (Prdx5) accelerates kidney fibrosis, a hallmark of CKD. This study aims to observe whether the deficiency of Prdx5 also contributes to the worsening of CKD-related hypertension. Angiotensin II (Ang II, 1000 ng/kg/day) was infused into Prdx5 wild-type (WT) and Prdx5 knock out (KO) mice (each group; n = 6). The blood pressure was higher in the Ang-II-infused Prdx5 KO mice than in the WT mice. Ang-II-induced ROS/RNS generation and fibrotic marker expressions were also higher in the Prdx5 KO mice. In particular, the expression of the sodium-chloride cotransporter (NCC), an ion transport protein important for sodium retention in the distal convoluted tubule, and the NCC's phosphorylation at Thr53 were increased in the kidney of Ang-II-infused Prdx5 KO. The activity of an WNK4-SPAK/OSR1, upstream activator of the NCC, was also increased. In 209/mDCT cells, the knockdown of Prdx5 (siPrdx5) increased the activity of Ang-II-mediated WNK4-SPAK/OSR1-NCC signaling and Ang-II-mediated ROS generation, whereas Prdx5 overexpression showed opposite results. In conclusion, Prdx5 negatively regulates the WNK4-SPAK/OSR1-NCC signaling axis, indicating its potential as a candidate for antihypertensive drug development through NCC regulation.
Collapse
Affiliation(s)
| | | | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School & Hospital, Gwangju 61469, Republic of Korea; (H.-I.C.); (I.A.J.)
| |
Collapse
|
10
|
Červenka L, Husková Z, Kikerlová S, Gawrys O, Vacková Š, Škaroupková P, Sadowski J, Miklovič M, Molnár M, Táborský M, Melenovský V, Bader M. Transgenic rat with ubiquitous expression of angiotensin-(1-7)-producing fusion protein: a new tool to study the role of protective arm of the renin-angiotensin system in the pathophysiology of cardio-renal diseases. Hypertens Res 2025; 48:336-352. [PMID: 39537982 PMCID: PMC11700845 DOI: 10.1038/s41440-024-01995-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.
Collapse
Affiliation(s)
- Luděk Červenka
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
- Department of Internal Medicine I, Cardiology, University Hospital Olomouc and Palacký University, Olomouc, Czech Republic.
| | - Zuzana Husková
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Soňa Kikerlová
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Olga Gawrys
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Šárka Vacková
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Petra Škaroupková
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Janusz Sadowski
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Matúš Miklovič
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Matej Molnár
- Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Pathophysiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Miloš Táborský
- Department of Internal Medicine I, Cardiology, University Hospital Olomouc and Palacký University, Olomouc, Czech Republic
| | - Vojtěch Melenovský
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Institute for Biology, University of Lübeck, Lübeck, Germany
- Charité University Medicine Berlin, Berlin, Germany
| |
Collapse
|
11
|
Badreh F, Joukar S, Badavi M, Rashno M. Fasting recovers age-related hypertension in the rats: reset of renal renin-angiotensin system components and klotho. BMC Nephrol 2024; 25:470. [PMID: 39716128 DOI: 10.1186/s12882-024-03918-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND The renal renin-angiotensin system (RAS) plays a vital part in the control of blood pressure and is known to be affected by aging. This study aimed to investigate the effects of intermittent fasting on age-related hypertension and the expression of local renal RAS components. METHODS The Wistar rats were categorized into three main age groups (young, middle aged, and elderly) and three dietary treatment models, including ad libitum feeding (AL), every other day fasting (EOD), and one day per week of fasting (FW). After three months, blood pressure (BP) was assessed. Some genes and proteins of the renal RAS system were measured by using Real time PCR and Western blot. α-klotho and Ang II proteins were assessed by ELISA method. RESULTS Old rats exhibited significantly increase in BP and Ang II (P < 0.001 vs. young rats) and a significant reduction in circulating levels of α-klotho and kidney AT2R protein (P < 0.001, P < 0.01, vs. young rats, respectively). Additionally, they respond to aging by increasing the AT1aR/AT2R proteins ratio (P < 0.05). Two model of feeding reduced BP in old rats and circulating Ang II in middle-aged and older rats. Moreover, by fasting, ACE2 protein expression was elevated in old rats. EOD fasting also significantly elevated the AT2 receptor protein and reduced the AT1aR/AT2R proteins ratio in the older rats (P < 0.001, P < 0.01, respectively). CONCLUSION Our findings suggest that fasting, particularly EOD, can attenuate age-related hypertension, partly through reset of the local renal RAS and increase of klotho protein expression.
Collapse
Affiliation(s)
- Firuzeh Badreh
- Behbahan Faculty of Medical Sciences, Behbahan, Iran
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Siyavash Joukar
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Science, P.O.Box 7616914115, Kerman, Iran.
| | - Mohammad Badavi
- Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- The Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Rashno
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
12
|
Arendshorst WJ, Vendrov AE, Kumar N, Ganesh SK, Madamanchi NR. Oxidative Stress in Kidney Injury and Hypertension. Antioxidants (Basel) 2024; 13:1454. [PMID: 39765782 PMCID: PMC11672783 DOI: 10.3390/antiox13121454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 01/11/2025] Open
Abstract
Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. Managing blood pressure (BP) effectively with treatments targeting RAAS activation, oxidative stress, and inflammation is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Interactions between genetic and environmental factors impacting kidney function abnormalities are central to HTN development. Animal studies indicate that genetic factors significantly influence BP regulation. Anti-natriuretic mechanisms can reset the pressure-natriuresis relationship, requiring a higher BP to excrete sodium matched to intake. Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. In HTN, the gut microbiome can affect BP by influencing energy metabolism and inflammatory pathways. Animal models, such as the spontaneously hypertensive rat and the chronic angiotensin II infusion model, mirror human essential hypertension and highlight the significance of the kidney in HTN pathogenesis. Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. Therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing oxidative stress, inflammation, and RAAS activity, offering renal and antihypertensive protection in managing HTN and CKD. This review emphasizes the critical role of NOX in the development and progression of HTN, focusing on its impact on renal function and BP regulation. Effective BP management and targeting oxidative stress, inflammation, and RAAS activation, is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD.
Collapse
Affiliation(s)
- Willaim J. Arendshorst
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Aleksandr E. Vendrov
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
| | - Nitin Kumar
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Santhi K. Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nageswara R. Madamanchi
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
| |
Collapse
|
13
|
Trueblood CT, Singh A, Cusimano MA, Hou S. Autonomic Dysreflexia in Spinal Cord Injury: Mechanisms and Prospective Therapeutic Targets. Neuroscientist 2024; 30:597-611. [PMID: 38084412 PMCID: PMC11166887 DOI: 10.1177/10738584231217455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Abstract
High-level spinal cord injury (SCI) often results in cardiovascular dysfunction, especially the development of autonomic dysreflexia. This disorder, characterized as an episode of hypertension accompanied by bradycardia in response to visceral or somatic stimuli, causes substantial discomfort and potentially life-threatening symptoms. The neural mechanisms underlying this dysautonomia include a loss of supraspinal control to spinal sympathetic neurons, maladaptive plasticity of sensory inputs and propriospinal interneurons, and excessive discharge of sympathetic preganglionic neurons. While neural control of cardiovascular function is largely disrupted after SCI, the renin-angiotensin system (RAS), which mediates blood pressure through hormonal mechanisms, is up-regulated after injury. Whether the RAS engages in autonomic dysreflexia, however, is still controversial. Regarding therapeutics, transplantation of embryonic presympathetic neurons, collected from the brainstem or more specific raphe regions, into the injured spinal cord may reestablish supraspinal regulation of sympathetic activity for cardiovascular improvement. This treatment reduces the occurrence of spontaneous autonomic dysreflexia and the severity of artificially triggered dysreflexic responses in rodent SCI models. Though transplanting early-stage neurons improves neural regulation of blood pressure, hormonal regulation remains high and baroreflex dysfunction persists. Therefore, cell transplantation combined with selected RAS inhibition may enhance neuroendocrine homeostasis for cardiovascular recovery after SCI.
Collapse
Affiliation(s)
- Cameron T. Trueblood
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Anurag Singh
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Marissa A. Cusimano
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Shaoping Hou
- Marion Murray Spinal Cord Research Center, Department of Neurobiology and Anatomy, College of Medicine, Drexel University, Philadelphia, PA, USA
| |
Collapse
|
14
|
Kruithof BPT, Mousavi Gourabi B, van de Merbel AF, DeRuiter MC, Goumans MJ. A New Ex Vivo Model to Study Cardiac Fibrosis in Whole Mouse Hearts. JACC Basic Transl Sci 2024; 9:1005-1022. [PMID: 39297130 PMCID: PMC11405901 DOI: 10.1016/j.jacbts.2024.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 09/21/2024]
Abstract
Fibrosis is a characteristic of many cardiac diseases for which no effective treatment exists. We have developed an ex vivo flow system, which allows induction of cardiac fibrosis in intact adult mouse hearts. Lineage-tracing studies indicated that the collagen-producing myofibroblasts originated from the resident fibroblasts. The extent of fibrosis was flow rate dependent, and pharmacological inhibition of the transforming growth factor beta signaling pathway prevented fibrosis. Therefore, in this powerful system, the cellular and molecular mechanisms underlying cardiac fibrosis can be studied. In addition, new targets can be tested on organ level for their ability to inhibit fibrosis.
Collapse
Affiliation(s)
- Boudewijn P T Kruithof
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Babak Mousavi Gourabi
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Marco C DeRuiter
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Marie-José Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| |
Collapse
|
15
|
McDermott JG, Goodlett BL, Creed HA, Navaneethabalakrishnan S, Rutkowski JM, Mitchell BM. Inflammatory Alterations to Renal Lymphatic Endothelial Cell Gene Expression in Mouse Models of Hypertension. Kidney Blood Press Res 2024; 49:588-604. [PMID: 38972305 PMCID: PMC11345939 DOI: 10.1159/000539721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
INTRODUCTION Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. METHODS We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. RESULTS Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p < 0.01), 274 significantly enriched pathways (p < 0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. CONCLUSION These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.
Collapse
Affiliation(s)
- Justin G. McDermott
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Bethany L. Goodlett
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Heidi A. Creed
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | | | - Joseph M. Rutkowski
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| |
Collapse
|
16
|
Aloss K, Hamar P. Augmentation of the EPR effect by mild hyperthermia to improve nanoparticle delivery to the tumor. Biochim Biophys Acta Rev Cancer 2024; 1879:189109. [PMID: 38750699 DOI: 10.1016/j.bbcan.2024.189109] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/05/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024]
Abstract
The clinical translation of the nanoparticle (NP)-based anticancer therapies is still unsatisfactory due to the heterogeneity of the enhanced permeability and retention (EPR) effect. Despite the promising preclinical outcome of the pharmacological EPR enhancers, their systemic toxicity can limit their clinical application. Hyperthermia (HT) presents an efficient tool to augment the EPR by improving tumor blood flow (TBF) and vascular permeability, lowering interstitial fluid pressure (IFP), and disrupting the structure of the extracellular matrix (ECM). Furthermore, the HT-triggered intravascular release approach can overcome the EPR effect. In contrast to pharmacological approaches, HT is safe and can be focused to cancer tissues. Moreover, HT conveys direct anti-cancer effects, which improve the efficacy of the anti-cancer agents encapsulated in NPs. However, the clinical application of HT is challenging due to the heterogeneous distribution of temperature within the tumor, the length of the treatment and the complexity of monitoring.
Collapse
Affiliation(s)
- Kenan Aloss
- Institute of Translational Medicine - Semmelweis University - 1094, Tűzoltó utca, 37-49, Budapest, Hungary
| | - Péter Hamar
- Institute of Translational Medicine - Semmelweis University - 1094, Tűzoltó utca, 37-49, Budapest, Hungary.
| |
Collapse
|
17
|
Yamani F, Cianfarini C, Batlle D. Delayed Graft Function and the Renin-angiotensin System. Transplantation 2024; 108:1308-1318. [PMID: 38361243 PMCID: PMC11136607 DOI: 10.1097/tp.0000000000004934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF.
Collapse
Affiliation(s)
- Fatmah Yamani
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Cosimo Cianfarini
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Daniel Batlle
- Division of Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| |
Collapse
|
18
|
Nishimoto M, Griffin KA, Wynne BM, Fujita T. Salt-Sensitive Hypertension and the Kidney. Hypertension 2024; 81:1206-1217. [PMID: 38545804 DOI: 10.1161/hypertensionaha.123.21369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Salt-sensitive hypertension (SS-HT) is characterized by blood pressure elevation in response to high dietary salt intake and is considered to increase the risk of cardiovascular and renal morbidity. Although the mechanisms responsible for SS-HT are complex, the kidneys are known to play a central role in the development of SS-HT and the salt sensitivity of blood pressure (SSBP). Moreover, several factors influence renal function and SSBP, including the renin-angiotensin-aldosterone system, sympathetic nervous system, obesity, and aging. A phenotypic characteristic of SSBP is aberrant activation of the renin-angiotensin system and sympathetic nervous system in response to excessive salt intake. SSBP is also accompanied by a blunted increase in renal blood flow after salt loading, resulting in sodium retention and SS-HT. Obesity is associated with inappropriate activation of the aldosterone mineralocorticoid receptor pathway and renal sympathetic nervous system in response to excessive salt, and mineralocorticoid receptor antagonists and renal denervation attenuate sodium retention and inhibit salt-induced blood pressure elevation in obese dogs and humans. SSBP increases with age, which has been attributed to impaired renal sodium handling and a decline in renal function, even in the absence of kidney disease. Aging-associated changes in renal hemodynamics are accompanied by significant alterations in renal hormone levels and renal sodium handling, resulting in SS-HT. In this review, we focus mainly on the contribution of renal function to the development of SS-HT.
Collapse
Affiliation(s)
- Mitsuhiro Nishimoto
- Department of Internal Medicine, Division of Nephrology & Hypertension, International University of Health and Welfare Mita Hospital, Tokyo, Japan (M.N.)
| | - Karen A Griffin
- Department of Medicine, Renal Disease & Hypertension, Loyola University, Chicago, IL (K.A.G.)
- Veteran's Administration, Nephrology, Edward Hines Jr. VA Hospital (K.A.G.)
| | - Brandi M Wynne
- Department of Internal Medicine, Nephrology & Hypertension, Department of Nutrition and Integrative Physiology, and Immunology, Inflammation and Infectious Disease Initiative (B.M.W.), University of Utah, Salt Lake City
| | - Toshiro Fujita
- Division of Clinical Epigenetics, Research Center for Advanced Science & Technology, The University of Tokyo, Japan (T.F.)
| |
Collapse
|
19
|
Becerra Calderon A, Shroff UN, Deepak S, Izuhara A, Trogen G, McDonough AA, Gurley SB, Nelson JW, Peti‐Peterdi J, Gyarmati G. Angiotensin II Directly Increases Endothelial Calcium and Nitric Oxide in Kidney and Brain Microvessels In Vivo With Reduced Efficacy in Hypertension. J Am Heart Assoc 2024; 13:e033998. [PMID: 38726925 PMCID: PMC11179802 DOI: 10.1161/jaha.123.033998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/15/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of angiotensin II on vascular endothelial cells (VECs) in vivo and the mechanisms how VECs may mitigate angiotensin II-mediated vasoconstriction are not fully understood. The present study aimed to explore the molecular mechanisms and pathophysiological relevance of the direct actions of angiotensin II on VECs in kidney and brain microvessels in vivo. METHODS AND RESULTS Changes in VEC intracellular calcium ([Ca2+]i) and nitric oxide (NO) production were visualized by intravital multiphoton microscopy of cadherin 5-Salsa6f mice or the endothelial uptake of NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, respectively. Kidney fibrosis by unilateral ureteral obstruction and Ready-to-use adeno-associated virus expressing Mouse Renin 1 gene (Ren1-AAV) hypertension were used as disease models. Acute systemic angiotensin II injections triggered >4-fold increases in VEC [Ca2+]i in brain and kidney resistance arterioles and capillaries that were blocked by pretreatment with the type 1 angiotensin II receptor inhibitor losartan, but not by the type 2 angiotensin II receptor inhibitor PD123319. VEC responded to acute angiotensin II by increased NO production as indicated by >1.5-fold increase in 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence intensity. In mice with kidney fibrosis or hypertension, the angiotensin II-induced VEC [Ca2+]i and NO responses were significantly reduced, which was associated with more robust vasoconstrictions, VEC shedding, and microthrombi formation. CONCLUSIONS The present study directly visualized angiotensin II-induced increases in VEC [Ca2+]i and NO production that serve to counterbalance agonist-induced vasoconstriction and maintain residual organ blood flow. These direct and endothelium-specific angiotensin II effects were blunted in disease conditions and linked to endothelial dysfunction and the development of vascular pathologies.
Collapse
Affiliation(s)
- Alejandra Becerra Calderon
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| | - Urvi Nikhil Shroff
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| | - Sachin Deepak
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| | - Audrey Izuhara
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| | - Greta Trogen
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| | - Alicia A. McDonough
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
| | - Susan B. Gurley
- Department of MedicineUniversity of Southern CaliforniaLos AngelesCA
| | | | - János Peti‐Peterdi
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
- Department of MedicineUniversity of Southern CaliforniaLos AngelesCA
| | - Georgina Gyarmati
- Department of Physiology and NeuroscienceUniversity of Southern CaliforniaLos AngelesCA
- Zilkha Neurogenetic InstituteUniversity of Southern CaliforniaLos AngelesCA
| |
Collapse
|
20
|
Daugherty A, Sawada H, Sheppard MB, Lu HS. Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases. Arterioscler Thromb Vasc Biol 2024; 44:1021-1030. [PMID: 38572647 PMCID: PMC11225801 DOI: 10.1161/atvbaha.124.318374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024]
Abstract
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
Collapse
Affiliation(s)
- Alan Daugherty
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY
- Saha Aortic Center, University of Kentucky, Lexington, KY
- Department of Physiology, University of Kentucky, Lexington, KY
| | - Hisashi Sawada
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY
- Saha Aortic Center, University of Kentucky, Lexington, KY
- Department of Physiology, University of Kentucky, Lexington, KY
| | - Mary B. Sheppard
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY
- Saha Aortic Center, University of Kentucky, Lexington, KY
- Department of Physiology, University of Kentucky, Lexington, KY
- Department of Family and Community Medicine, University of Kentucky, Lexington, KY
- Department of Surgery, University of Kentucky, Lexington, KY
| | - Hong S. Lu
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY
- Saha Aortic Center, University of Kentucky, Lexington, KY
- Department of Physiology, University of Kentucky, Lexington, KY
| |
Collapse
|
21
|
Wan Y, He S, Xu T, Wang S, Qi M, Gan P. The Role of Angiotensin II Receptor Blockers in the Management of Hypertrophic Cardiomyopathy: An Updated Meta-Analysis of Randomized Controlled Trials. Cardiology 2024; 149:632-642. [PMID: 38599198 DOI: 10.1159/000538638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/28/2024] [Indexed: 04/12/2024]
Abstract
INTRODUCTION The use of angiotensin II receptor blockers (ARBs) in the treatment of hypertrophic cardiomyopathy (HCM) remains a subject of controversy. METHODS We conducted a comprehensive search of the Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov, and Web of Science databases until October 2023 to identify articles investigating the effects of ARBs in patients diagnosed with HCM. Predefined criteria were utilized for selecting data on study characteristics and results. RESULTS The study included a total of 387 patients from 6 randomized controlled trials, which were reported in 7 articles. The results of the meta-analysis revealed that the utilization of ARBs did not yield a reduction in left ventricular (LV) mass (p = 0.07) and maximum LV wall thickness (p = 0.25), nor did it demonstrate any improvement in LV fibrosis (p = 0.39). Furthermore, there was no significant impact observed on early diastolic mitral annular velocity (p = 0.19) and LV ejection fraction (p = 0.44). CONCLUSIONS The administration of ARBs does not appear to yield improvements in cardiac structure, function, and myocardial fibrosis in patients with HCM.
Collapse
Affiliation(s)
- Yong Wan
- Department of Endocrinology, Hangzhou Linping Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Shuai He
- Department of Hand and Foot Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Tingli Xu
- Department of Intensive Care Rehabilitation, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Shuwei Wang
- Department of Intensive Care Rehabilitation, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Minfang Qi
- Department of Intensive Care Rehabilitation, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Pengcheng Gan
- Department of Intensive Care Rehabilitation, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| |
Collapse
|
22
|
Kij A, Bar A, Czyzynska-Cichon I, Przyborowski K, Proniewski B, Mateuszuk L, Kurylowicz Z, Jasztal A, Buczek E, Kurpinska A, Suraj-Prazmowska J, Marczyk B, Matyjaszczyk-Gwarda K, Daiber A, Oelze M, Walczak M, Chlopicki S. Vascular protein disulfide isomerase A1 mediates endothelial dysfunction induced by angiotensin II in mice. Acta Physiol (Oxf) 2024; 240:e14116. [PMID: 38400621 DOI: 10.1111/apha.14116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024]
Abstract
AIM Protein disulfide isomerases (PDIs) are involved in platelet aggregation and intravascular thrombosis, but their role in regulating endothelial function is unclear. Here, we characterized the involvement of vascular PDIA1 in angiotensin II (Ang II)-induced endothelial dysfunction in mice. METHODS Endothelial dysfunction was induced in C57BL/6JCmd male mice via Ang II subcutaneous infusion, and PDIA1 was inhibited with bepristat. Endothelial function was assessed in vivo with magnetic resonance imaging and ex vivo with a myography, while arterial stiffness was measured as pulse wave velocity. Nitric oxide (NO) bioavailability was measured in the aorta (spin-trapping electron paramagnetic resonance) and plasma (NO2 - and NO3 - levels). Oxidative stress, eNOS uncoupling (DHE-based aorta staining), and thrombin activity (thrombin-antithrombin complex; calibrated automated thrombography) were evaluated. RESULTS The inhibition of PDIA1 by bepristat in Ang II-treated mice prevented the impairment of NO-dependent vasodilation in the aorta as evidenced by the response to acetylcholine in vivo, increased systemic NO bioavailability and the aortic NO production, and decreased vascular stiffness. Bepristat's effect on NO-dependent function was recapitulated ex vivo in Ang II-induced endothelial dysfunction in isolated aorta. Furthermore, bepristat diminished the Ang II-induced eNOS uncoupling and overproduction of ROS without affecting thrombin activity. CONCLUSION In Ang II-treated mice, the inhibition of PDIA1 normalized the NO-ROS balance, prevented endothelial eNOS uncoupling, and, thereby, improved vascular function. These results indicate the importance of vascular PDIA1 in regulating endothelial function, but further studies are needed to elucidate the details of the mechanisms involved.
Collapse
Affiliation(s)
- Agnieszka Kij
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Anna Bar
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Izabela Czyzynska-Cichon
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Kamil Przyborowski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Bartosz Proniewski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Lukasz Mateuszuk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Zuzanna Kurylowicz
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Elzbieta Buczek
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Anna Kurpinska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Joanna Suraj-Prazmowska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | - Brygida Marczyk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
| | | | - Andreas Daiber
- Laboratory of Molecular Cardiology, Department of Cardiology 1, The Center for Cardiology, University Medical Center, Mainz, Germany
| | - Matthias Oelze
- Laboratory of Molecular Cardiology, Department of Cardiology 1, The Center for Cardiology, University Medical Center, Mainz, Germany
| | - Maria Walczak
- Department of Toxicology, Jagiellonian University Medical College, Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
23
|
Budzyń M, Gryszczyńska B, Begier-Krasińska B, Kaja E, Mikołajczak P, Kujawski R, Grupińska J, Iskra M, Tykarski A, Kaczmarek M. Decreased toll-like receptor 4 and CD11b/CD18 expression on peripheral monocytes of hypertensive patients correlates with a lesser extent of endothelial damage: a preliminary study. J Hypertens 2024; 42:471-483. [PMID: 37937521 DOI: 10.1097/hjh.0000000000003617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
BACKGROUND Low-grade chronic inflammation is recognized to contribute to the physiopathology of arterial hypertension. Therefore, this study aimed to assess the pro-inflammatory phenotype of peripheral monocytes of hypertensive patients by analyzing Toll-like receptor 4 (TLR4) and CD11b/CD18 surface expression. In the second part, the influence of phenotypic alterations of monocytes on the endothelial status reflected by circulating endothelial cells (CECs) was evaluated. PATIENTS The study included 60 patients with arterial hypertension, who were divided into two subgroups based on the disease severity according to the applicable criteria. The mild hypertension and resistant hypertension groups included 30 patients each. The control group consisted of 33 normotensive volunteers matched for age and sex. RESULTS Both in the entire group of patients and individual subgroups, reduced surface expression of TLR4 and CD11b/CD18 was found compared to normotensive volunteers. A reduced percentage of monocytes with the CD14 + TLR4 + immunophenotype was correlated with a lower MFI level of CD18 and CD11b in the entire group of patients and after division only in the mild hypertension group. Reduced surface expression of TLR4 in hypertensive patients correlated with a lower number of CECs. This relationship was not observed in the resistant hypertension group; instead, an independent effect of reduced CD11b/CD18 expression on the reduction of CEC number was demonstrated. CONCLUSION Our preliminary study showed for the first time that hypertension of varying severity is accompanied by phenotypic changes in monocytes, manifested by reduced surface expression of both TLR4 and CD11b/CD18. These phenotypic changes were associated with a reduced degree of endothelial injury. Our study opens a new, unexplored area of research on the protective features of peripheral monocytes in hypertension.
Collapse
Affiliation(s)
- Magdalena Budzyń
- Chair and Department of Medical Chemistry and Laboratory Medicine
| | | | | | - Elżbieta Kaja
- Chair and Department of Medical Chemistry and Laboratory Medicine
| | | | | | - Joanna Grupińska
- Chair and Department of Medical Chemistry and Laboratory Medicine
| | - Maria Iskra
- Chair and Department of Medical Chemistry and Laboratory Medicine
| | | | - Mariusz Kaczmarek
- Department of Cancer Immunology, Poznan University of Medical Sciences
- Gene Therapy Unit, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Center, Poznan, Poland
| |
Collapse
|
24
|
Ahn YM, Kim HY, Kang DG, Cho KW, Lee HS. Herbal medicine (Oryeongsan) for fluid and sodium balance in renal cortex of spontaneously hypertensive rats. Integr Med Res 2024; 13:101007. [PMID: 38298863 PMCID: PMC10826321 DOI: 10.1016/j.imr.2023.101007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 11/02/2023] [Accepted: 11/13/2023] [Indexed: 02/02/2024] Open
Abstract
Background Herbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinesehas been used for the treatment of impaired body fluid balance. However, the mechanisms involved are not clearly defined. The purpose of the present study was to identify the actions of ORS on the renal excretory function and blood pressure (BP) and to define the mechanisms involved in association with renin-angiotensin system (RAS) and natriuretic peptide system (NPS) in spontaneously hypertensive rats (SHR), an animal model of human essential hypertension. Methods Changes in urine volume (UV), excretion of electrolytes including Na+ (urinary excretion of Na+ (UNaV)) were measured. RT-PCR was performed to trace the changes in expression of RAS, NPS and sodium (Na+)-hydrogen (H+) exchanger 3 (NHE3) in the renal cortex. Results In the SHR treated with vehicle (SHR-V) group, UV and UNaV were suppressed and the Na+ balance was maintained at the higher levels leading to an increase in BP compared to WKY-V group. These were accompanied by an increase in NHE3 expression with an accentuation of angiotensin I converting enzyme-angiotensin II type 1 (ACE-AT1) receptor and concurrent suppression of angiotensin II type 2 (AT2) receptor/ACE2-Mas receptor expression in the renal cortex. Chronic treatment with ORS increased UV and UNaV, and decreased the Na+ and water balance with a decrease in BP in the ORS-treated SHR-ORS group compared to SHR-V. These were accompanied by a decrease in NHE3 expression with a suppression of ACE-AT1 receptor and concurrent accentuation of AT2/ACE2-Mas receptor. Conclusion The present study shows that ORS reduced BP with a decrease in Na+ and water retention by a suppression of NHE3 expression via modulation of RAS and NPS in SHR. The present study provides pharmacological rationale for the treatment of hypertension with ORS in SHR.
Collapse
Affiliation(s)
- You Mee Ahn
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Hye Yoom Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Dae Gill Kang
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
| | - Kyung Woo Cho
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
| | - Ho Sub Lee
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
- College of Korean Medicine and Professional Graduate School of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
| |
Collapse
|
25
|
He X, Williams QA, Cantrell AC, Besanson J, Zeng H, Chen JX. TIGAR Deficiency Blunts Angiotensin-II-Induced Cardiac Hypertrophy in Mice. Int J Mol Sci 2024; 25:2433. [PMID: 38397106 PMCID: PMC10889085 DOI: 10.3390/ijms25042433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy.
Collapse
Affiliation(s)
| | | | | | | | - Heng Zeng
- Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (X.H.); (Q.A.W.); (A.C.C.); (J.B.)
| | - Jian-Xiong Chen
- Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; (X.H.); (Q.A.W.); (A.C.C.); (J.B.)
| |
Collapse
|
26
|
Liberona J, Araos P, Rodríguez M, León P, Stutzin A, Alzamora R, Michea L. Low-Chloride Diet Prevents the Development of Arterial Hypertension and Protects Kidney Function in Angiotensin II-Infused Mice. Kidney Blood Press Res 2024; 49:114-123. [PMID: 38246148 DOI: 10.1159/000535728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/06/2023] [Indexed: 01/23/2024] Open
Abstract
INTRODUCTION A comprehensive pathophysiological mechanism to explain the relationship between high-salt intake and hypertension remains undefined. Evidence suggests that chloride, as the accompanying anion of sodium in dietary salt, is necessary to develop hypertension. We evaluated whether reducing dietary Cl- while keeping a standard Na+ intake modified blood pressure, cardiac hypertrophy, renal function, and vascular contractility after angiotensin II (AngII) infusion. METHODS C56BL/6J mice fed with standard Cl- diet or a low-Cl- diet (equimolar substitution of Cl- by a mixture of Na+ salts, both diets with standard Na+ content) received AngII (infusion of 1.5 mg/kg/day) or vehicle for 14 days. We measured systolic blood pressure (SBP), glomerular filtration rate (GFR), natriuretic response to acute saline load, and contractility of aortic rings from mice infused with vehicle and AngII, in standard and low-Cl- diet. RESULTS The mice fed the standard diet presented increased SBP and cardiac hypertrophy after AngII infusion. In contrast, low-Cl- diet prevented the increase of SBP and cardiac hypertrophy. AngII-infused mice fed a standard diet presented hampered natriuretic response to saline load, meanwhile the low-Cl- diet preserved natriuretic response in AngII-infused mice, without change in GFR. Aortic rings from mice fed with standard diet or low-Cl- diet and infused with AngII presented a similar contractile response. CONCLUSION We conclude that the reduction in dietary Cl- as the accompanying anion of sodium in salt is protective from AngII pro-hypertensive actions due to a beneficial effect on kidney function and preserved natriuresis.
Collapse
Affiliation(s)
- Jessica Liberona
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile,
| | - Patricio Araos
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Marcelo Rodríguez
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Pablo León
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Andrés Stutzin
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago, Chile
| | - Rodrigo Alzamora
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Anestesiología y Medicina Perioperatoria, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Luis Michea
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Medicina Interna Norte, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| |
Collapse
|
27
|
Raj R, Garg M, Kaur A. Targeting Hypertension: A Review on Pathophysiological Factors and Treatment Strategies. Curr Hypertens Rev 2024; 20:70-79. [PMID: 38509679 DOI: 10.2174/0115734021293403240309165336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/22/2024]
Abstract
Hypertension is one of the primary causes of cardiovascular diseases and death, with a higher prevalence in low- and middle-income countries. The pathophysiology of hypertension remains complex, with 2% to 5% of patients having underlying renal or adrenal disorders. The rest are referred to as essential hypertension, with derangements in various physiological mechanisms potentially contributing to the development of essential hypertension. Hypertension elevates the risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and mortality. First-line therapy for hypertension is lifestyle change, which includes weight loss, a balanced diet that includes low salt and high potassium intake, physical exercise, and limitation or elimination of alcohol use. Blood pressure-lowering effects of individual lifestyle components are partially additive, enhancing the efficacy of pharmaceutical treatment. The choice to begin antihypertensive medication should be based on the level of blood pressure and the existence of a high atherosclerotic CVD risk. First-line hypertension treatment includes a thiazide or thiazide-like diuretic, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocker. Addressing hypertension will require continued efforts to improve access to diagnosis, treatment, and lifestyle interventions.
Collapse
Affiliation(s)
- Ruhani Raj
- Department of Biotechnology, UIET, Panjab University, Chandigarh, India
| | - Minakshi Garg
- Department of Biotechnology, UIET, Panjab University, Chandigarh, India
| | - Anupreet Kaur
- Department of Biotechnology, UIET, Panjab University, Chandigarh, India
| |
Collapse
|
28
|
Dorey TW, McRae MD, Belke DD, Rose RA. PDE4D mediates impaired β-adrenergic receptor signalling in the sinoatrial node in mice with hypertensive heart disease. Cardiovasc Res 2023; 119:2697-2711. [PMID: 37643895 PMCID: PMC10757582 DOI: 10.1093/cvr/cvad138] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 06/06/2023] [Accepted: 07/18/2023] [Indexed: 08/31/2023] Open
Abstract
AIMS The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease. METHODS AND RESULTS C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice. CONCLUSIONS AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.
Collapse
Affiliation(s)
- Tristan W Dorey
- Libin Cardiovascular Institute, Department of Cardiac Sciences, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Megan D McRae
- Libin Cardiovascular Institute, Department of Cardiac Sciences, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Darrell D Belke
- Libin Cardiovascular Institute, Department of Cardiac Sciences, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Robert A Rose
- Libin Cardiovascular Institute, Department of Cardiac Sciences, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| |
Collapse
|
29
|
Cappelletti P, Gallo G, Marino R, Palaniappan S, Corbo M, Savoia C, Feligioni M. From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection. Eur J Pharmacol 2023; 959:176061. [PMID: 37775018 DOI: 10.1016/j.ejphar.2023.176061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 10/01/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.
Collapse
Affiliation(s)
- Pamela Cappelletti
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy.
| | - Giovanna Gallo
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Rachele Marino
- European Brain Research Institute (EBRI) Rita Levi Montalcini Foundation, Rome, Italy
| | | | - Massimo Corbo
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy
| | - Carmine Savoia
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Marco Feligioni
- Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy; European Brain Research Institute (EBRI) Rita Levi Montalcini Foundation, Rome, Italy.
| |
Collapse
|
30
|
Alla JA, Nerger E, Langer A, Quitterer U. Identification of membrane palmitoylated protein 1 (MPP1) as a heart-failure-promoting protein triggered by cardiovascular risk factors and aging. Biochem Pharmacol 2023; 217:115789. [PMID: 37683843 DOI: 10.1016/j.bcp.2023.115789] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/10/2023]
Abstract
Membrane-Associated Guanylate Kinase (MAGUK) proteins are scaffold proteins with well-established functions in the neuronal system. A role of MAGUK protein up-regulation in the pathogenesis of heart failure is not established. This study identified the up-regulation of the MAGUK family protein MPP1 (Membrane Palmitoylated Protein 1), in cardiac transcriptome data of three different heart failure models. MPP1 was up-regulated in failing hearts of B6 mice with long-term chronic pressure overload, in failing hearts of aged Apoe-/- mice with long-term atherosclerosis, and in failing hearts of RKIP-transgenic mice with cardiotoxic lipid overload. MPP1-transgenic mice revealed that moderately (2-fold) increased cardiac MPP1 levels caused symptoms of heart failure with a significantly reduced left ventricular ejection fraction of 39.0 ± 6.9 % in Tg-MPP1 mice compared to 55.2 ± 3.7 % of non-transgenic B6 controls. Echocardiographic and histological analyses detected cardiac enlargement and cardiac dilation in Tg-MPP1 mice. The angiotensin II AT1 receptor (AGTR1) and MPP1 were co-localized on sarcolemmal membranes in vivo, and Tg-MPP1 mice had increased levels of cardiac AGTR1, which has an established heart failure-promoting function. The increased AGTR1 protein could be directly triggered by elevated MPP1 because MPP1 also increased the AGTR1 protein in non-cardiomyocyte HEK cells, which was detected by fluorescence measurement of AGTR1eYFP. MPP1 was not only up-regulated by major cardiovascular risk factors but also by old age, which is a major contributor to heart failure. Thus, the aging-induced MPP1 exerts a previously unrecognized role in heart failure pathogenesis by upregulation of the angiotensin II AT1 receptor (AGTR1) protein.
Collapse
Affiliation(s)
- Joshua Abd Alla
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| | - Eric Nerger
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Andreas Langer
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
| | - Ursula Quitterer
- Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland
| |
Collapse
|
31
|
Gamba G. Thirty years of the NaCl cotransporter: from cloning to physiology and structure. Am J Physiol Renal Physiol 2023; 325:F479-F490. [PMID: 37560773 PMCID: PMC10639029 DOI: 10.1152/ajprenal.00114.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
The primary structure of the thiazide-sensitive NaCl cotransporter (NCC) was resolved 30 years ago by the molecular identification of the cDNA encoding this cotransporter, from the winter's flounder urinary bladder, following a functional expression strategy. This review outlines some aspects of how the knowledge about thiazide diuretics and NCC evolved, the history of the cloning process, and the expansion of the SLC12 family of electroneutral cotransporters. The diseases associated with activation or inactivation of NCC are discussed, as well as the molecular model by which the activity of NCC is regulated. The controversies in the field are discussed as well as recent publication of the three-dimensional model of NCC obtained by cryo-electron microscopy, revealing not only the amino acid residues critical for Na+ and Cl- translocation but also the residues critical for polythiazide binding to the transporter, opening the possibility for a new era in thiazide diuretic therapy.
Collapse
Affiliation(s)
- Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| |
Collapse
|
32
|
Smart CD, Madhur MS. The immunology of heart failure with preserved ejection fraction. Clin Sci (Lond) 2023; 137:1225-1247. [PMID: 37606086 PMCID: PMC10959189 DOI: 10.1042/cs20230226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/23/2023] [Accepted: 07/31/2023] [Indexed: 08/23/2023]
Abstract
Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of new heart failure diagnoses and continues to increase in prevalence in the United States. Importantly, HFpEF is a highly morbid, heterogeneous syndrome lacking effective therapies. Inflammation has emerged as a potential contributor to the pathogenesis of HFpEF. Many of the risk factors for HFpEF are also associated with chronic inflammation, such as obesity, hypertension, aging, and renal dysfunction. A large amount of preclinical evidence suggests that immune cells and their associated cytokines play important roles in mediating fibrosis, oxidative stress, metabolic derangements, and endothelial dysfunction, all potentially important processes in HFpEF. How inflammation contributes to HFpEF pathogenesis, however, remains poorly understood. Recently, a variety of preclinical models have emerged which may yield much needed insights into the causal relationships between risk factors and the development of HFpEF, including the role of specific immune cell subsets or inflammatory pathways. Here, we review evidence in animal models and humans implicating inflammation as a mediator of HFpEF and identify gaps in knowledge requiring further study. As the understanding between inflammation and HFpEF evolves, it is hoped that a better understanding of the mechanisms underlying immune cell activation in HFpEF can open up new therapeutic avenues.
Collapse
Affiliation(s)
- Charles Duncan Smart
- Department of Molecular Physiology and Biophysics,
Vanderbilt University School of Medicine, Nashville, TN, U.S.A
| | - Meena S. Madhur
- Department of Molecular Physiology and Biophysics,
Vanderbilt University School of Medicine, Nashville, TN, U.S.A
- Department of Medicine, Division of Cardiovascular
Medicine, Vanderbilt University Medical Center, Nashville, TN, U.S.A
- Department of Medicine, Division of Clinical Pharmacology,
Vanderbilt University Medical Center, Nashville, TN, U.S.A
- Vanderbilt Institute for Infection, Immunology, and
Inflammation, Nashville, TN, U.S.A
| |
Collapse
|
33
|
Xu C. Cardiovascular aspects of ELABELA: A potential diagnostic biomarker and therapeutic target. Vascul Pharmacol 2023; 151:107193. [PMID: 37433415 DOI: 10.1016/j.vph.2023.107193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/19/2023] [Accepted: 07/05/2023] [Indexed: 07/13/2023]
Abstract
ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has been known as an important regulator in cardiovascular homeostasis and may be a novel therapeutic target for multiple cardiovascular diseases (CVDs). At the physiological level, ELABELA exhibits angiogenic and vasorelaxant effects and is essential for heart development. At the pathological level, circulating ELABELA levels may be a novel diagnostic biomarker for various CVDs. ELABELA peripherally displays antihypertensive, vascular-protective, and cardioprotective effects, whereas central administration of ELABELA elevated BP and caused cardiovascular remodeling. This review highlights the physiological and pathological roles of ELABELA in the cardiovascular system. Enhancement of the peripheral ELABELA may be a promising pharmacological therapeutic strategy for CVDs.
Collapse
Affiliation(s)
- Chuanming Xu
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang 330002, Jiangxi, China.
| |
Collapse
|
34
|
Perrotta M, Carnevale D, Carnevale L. Mouse models of cerebral injury and cognitive impairment in hypertension. Front Aging Neurosci 2023; 15:1199612. [PMID: 37539342 PMCID: PMC10394515 DOI: 10.3389/fnagi.2023.1199612] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023] Open
Abstract
Hypertension is a major risk factor for dementia, including both vascular and neurodegenerative etiologies. With the original aim of studying the effect of blood pressure elevation on canonical target organs of hypertension as the heart, the vasculature or the kidneys, several experimental models of hypertension have sprouted during the years. With the more recent interest of understanding the cerebral injury burden caused by hypertension, it is worth understanding how the main models of hypertension or localized cerebral hypertension stand in the field of hypertension-induced cerebral injury and cognitive impairment. With this review we will report main genetic, pharmacological and surgical models of cognitive impairment induced by hypertension, summarizing how each specific category and model can improve our understanding of the complex phenomenon of cognitive loss of vascular etiology.
Collapse
Affiliation(s)
- Marialuisa Perrotta
- Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
- Research Unit of Neuro and Cardiovascular Pathophysiology, IRCCS Neuromed, Department of Angiocardioneurology and Translational Medicine, Pozzilli, Italy
| | - Daniela Carnevale
- Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
- Research Unit of Neuro and Cardiovascular Pathophysiology, IRCCS Neuromed, Department of Angiocardioneurology and Translational Medicine, Pozzilli, Italy
| | - Lorenzo Carnevale
- Research Unit of Neuro and Cardiovascular Pathophysiology, IRCCS Neuromed, Department of Angiocardioneurology and Translational Medicine, Pozzilli, Italy
| |
Collapse
|
35
|
Kulthinee S, Tasanarong A, Franco M, Navar LG. Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension. Int J Mol Sci 2023; 24:11413. [PMID: 37511174 PMCID: PMC10380633 DOI: 10.3390/ijms241411413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/09/2023] [Indexed: 07/30/2023] Open
Abstract
In angiotensin II (Ang II)-dependent hypertension, Ang II activates angiotensin II type 1 receptors (AT1R) on renal vascular smooth muscle cells, leading to renal vasoconstriction with eventual glomerular and tubular injury and interstitial inflammation. While afferent arteriolar vasoconstriction is initiated by the increased intrarenal levels of Ang II activating AT1R, the progressive increases in arterial pressure stimulate the paracrine secretion of adenosine triphosphate (ATP), leading to the purinergic P2X receptor (P2XR)-mediated constriction of afferent arterioles. Thus, the afferent arteriolar tone is maintained by two powerful systems eliciting the co-existing activation of P2XR and AT1R. This raises the conundrum of how the AT1R and P2XR can both be responsible for most of the increased renal afferent vascular resistance existing in angiotensin-dependent hypertension. Its resolution implies that AT1R and P2XR share common receptor or post receptor signaling mechanisms which converge to maintain renal vasoconstriction in Ang II-dependent hypertension. In this review, we briefly discuss (1) the regulation of renal afferent arterioles in Ang II-dependent hypertension, (2) the interaction of AT1R and P2XR activation in regulating renal afferent arterioles in a setting of hypertension, (3) mechanisms regulating ATP release and effect of angiotensin II on ATP release, and (4) the possible intracellular pathways involved in AT1R and P2XR interactions. Emerging evidence supports the hypothesis that P2X1R, P2X7R, and AT1R actions converge at receptor or post-receptor signaling pathways but that P2XR exerts a dominant influence abrogating the actions of AT1R on renal afferent arterioles in Ang II-dependent hypertension. This finding raises clinical implications for the design of therapeutic interventions that will prevent the impairment of kidney function and subsequent tissue injury.
Collapse
Affiliation(s)
- Supaporn Kulthinee
- Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Adis Tasanarong
- Chulabhorn International College of Medicine, Thammasat University, Klong Luang 12120, Thailand
| | - Martha Franco
- Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico City 14080, Mexico
| | - Luis Gabriel Navar
- Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA
| |
Collapse
|
36
|
Thimm C, Erichsen L, Wruck W, Adjaye J. Unveiling Angiotensin II and Losartan-Induced Gene Regulatory Networks Using Human Urine-Derived Podocytes. Int J Mol Sci 2023; 24:10551. [PMID: 37445727 DOI: 10.3390/ijms241310551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin-angiotensin-aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases.
Collapse
Affiliation(s)
- Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Lars Erichsen
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Wasco Wruck
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
- EGA Institute for Women's Health, Zayed Centre for Research into Rare Diseases in Children (ZCR), University College London (UCL), 20 Guilford Street, London WC1N 1DZ, UK
| |
Collapse
|
37
|
Sharma A, Choi JSY, Watson AMD, Li L, Sonntag T, Lee MKS, Murphy AJ, De Blasio M, Head GA, Ritchie RH, de Haan JB. Cardiovascular characterisation of a novel mouse model that combines hypertension and diabetes co-morbidities. Sci Rep 2023; 13:8741. [PMID: 37253814 DOI: 10.1038/s41598-023-35680-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/22/2023] [Indexed: 06/01/2023] Open
Abstract
Epidemiologic data suggest that the prevalence of hypertension in patients with diabetes mellitus is ∼1.5-2.0 times greater than in matched non-diabetic patients. This co-existent disease burden exacerbates cardiac and vascular injury, leading to structural and functional changes to the myocardium, impaired cardiac function and heart failure. Oxidative stress and persistent low-grade inflammation underlie both conditions, and are identified as major contributors to pathological cardiac remodelling. There is an urgent need for effective therapies that specifically target oxidative stress and inflammation to protect against cardiac remodelling. Animal models are a valuable tool for testing emerging therapeutics, however, there is a notable lack of appropriate animal models of co-morbid diabetes and hypertension. In this study, we describe a novel preclinical mouse model combining diabetes and hypertension to investigate cardiac and vascular pathology of co-morbid disease. Type 1 diabetes was induced in spontaneously hypertensive, 8-week old, male Schlager (BPH/2) mice via 5 consecutive, daily injections of streptozotocin (55 mg/kg in citrate buffer; i.p.). Non-diabetic mice received citrate buffer only. After 10 weeks of diabetes induction, cardiac function was assessed by echocardiography prior to post-mortem evaluation of cardiomyocyte hypertrophy, interstitial fibrosis and inflammation by histology, RT-PCR and flow cytometry. We focussed on the oxidative and inflammatory stress pathways that contribute to cardiovascular remodelling. In particular, we demonstrate that markers of inflammation (monocyte chemoattractant protein; MCP-1), oxidative stress (urinary 8-isoprostanes) and fibrosis (connective tissue growth factor; CTGF) are significantly increased, whilst diastolic dysfunction, as indicated by prolonged isovolumic relaxation time (IVRT), is elevated in this diabetic and hypertensive mouse model. In summary, this pre-clinical mouse model provides researchers with a tool to test therapeutic strategies unique to co-morbid diabetes and hypertension, thereby facilitating the emergence of novel therapeutics to combat the cardiovascular consequences of these debilitating co-morbidities.
Collapse
Affiliation(s)
- Arpeeta Sharma
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia.
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
| | - Judy S Y Choi
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Anna M D Watson
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Cardiometabolic Health, University of Melbourne, Parkville, Australia
| | - Leila Li
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Thomas Sonntag
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Man K S Lee
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Andrew J Murphy
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Miles De Blasio
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Geoffrey A Head
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Rebecca H Ritchie
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Judy B de Haan
- Group Leader (Oxidative Stress Laboratory), Diabetic Complications Division, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Australia
- Faculty of Science, Engineering and Technology, Swinburne University, Melbourne, Australia
- Department of Cardiometabolic Health, University of Melbourne, Parkville, Australia
| |
Collapse
|
38
|
Grogan A, Lucero EY, Jiang H, Rockman HA. Pathophysiology and pharmacology of G protein-coupled receptors in the heart. Cardiovasc Res 2023; 119:1117-1129. [PMID: 36534965 PMCID: PMC10202650 DOI: 10.1093/cvr/cvac171] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 08/10/2023] Open
Abstract
G protein-coupled receptors (GPCRs), comprising the largest superfamily of cell surface receptors, serve as fundamental modulators of cardiac health and disease owing to their key roles in the regulation of heart rate, contractile dynamics, and cardiac function. Accordingly, GPCRs are heavily pursued as drug targets for a wide variety of cardiovascular diseases ranging from heart failure, cardiomyopathy, and arrhythmia to hypertension and coronary artery disease. Recent advancements in understanding the signalling mechanisms, regulation, and pharmacological properties of GPCRs have provided valuable insights that will guide the development of novel therapeutics. Herein, we review the cellular signalling mechanisms, pathophysiological roles, and pharmacological developments of the major GPCRs in the heart, highlighting the β-adrenergic, muscarinic, and angiotensin receptors as exemplar subfamilies.
Collapse
Affiliation(s)
- Alyssa Grogan
- Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA
| | - Emilio Y Lucero
- Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA
| | - Haoran Jiang
- Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA
| | - Howard A Rockman
- Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA
- Cell Biology, Duke University Medical Center, DUMC 3104, 226 CARL Building, 12 Durham, NC 27710, USA
| |
Collapse
|
39
|
Tang X, Lai CH, Malhi NK, Chadha R, Luo Y, Liu X, Yuan D, Tapia A, Abdollahi M, Zhang G, Calandrelli R, Shiu YT, Wang ZV, Rhee JW, Zhong S, Natarajan R, Chen ZB. Genetic Deletion of the LINC00520 Homolog in Mouse Aggravates Angiotensin II-Induced Hypertension. Noncoding RNA 2023; 9:31. [PMID: 37218991 PMCID: PMC10204496 DOI: 10.3390/ncrna9030031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 05/24/2023] Open
Abstract
(1) Background: Hypertension is a complex, multifactorial disease that is caused by genetic and environmental factors. Apart from genetic predisposition, the mechanisms involved in this disease have yet to be fully understood. We previously reported that LEENE (lncRNA enhancing endothelial nitric oxide expression, transcribed from LINC00520 in the human genome) regulates endothelial cell (EC) function by promoting the expression of endothelial nitric oxide synthase (eNOS) and vascular growth factor receptor 2 (VEGFR2). Mice with genetic deletion of the LEENE/LINC00520 homologous region exhibited impaired angiogenesis and tissue regeneration in a diabetic hindlimb ischemia model. However, the role of LEENE in blood pressure regulation is unknown. (2) Methods: We subjected mice with genetic ablation of leene and wild-type littermates to Angiotensin II (AngII) and monitored their blood pressure and examined their hearts and kidneys. We used RNA-sequencing to identify potential leene-regulated molecular pathways in ECs that contributed to the observed phenotype. We further performed in vitro experiments with murine and human ECs and ex vivo experiments with murine aortic rings to validate the select mechanism. (3) Results: We identified an exacerbated hypertensive phenotype of leene-KO mice in the AngII model, evidenced by higher systolic and diastolic blood pressure. At the organ level, we observed aggravated hypertrophy and fibrosis in the heart and kidney. Moreover, the overexpression of human LEENE RNA, in part, restored the signaling pathways impaired by leene deletion in murine ECs. Additionally, Axitinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR suppresses LEENE in human ECs. (4) Conclusions: Our study suggests LEENE as a potential regulator in blood pressure control, possibly through its function in ECs.
Collapse
Affiliation(s)
- Xiaofang Tang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Chih-Hung Lai
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 40705, Taiwan
| | - Naseeb K. Malhi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Rahuljeet Chadha
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91010, USA
| | - Yingjun Luo
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Xuejing Liu
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Dongqiang Yuan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Alonso Tapia
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Maryam Abdollahi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Guangyu Zhang
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Riccardo Calandrelli
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Yan-Ting Shiu
- Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT 84132, USA
- Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT 84132, USA
| | - Zhao V. Wang
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - June-Wha Rhee
- Department of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Sheng Zhong
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Zhen Bouman Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| |
Collapse
|
40
|
Ajoolabady A, Pratico D, Vinciguerra M, Lip GYH, Franceschi C, Ren J. Inflammaging: mechanisms and role in the cardiac and vasculature. Trends Endocrinol Metab 2023; 34:373-387. [PMID: 37076375 DOI: 10.1016/j.tem.2023.03.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/04/2023] [Accepted: 03/16/2023] [Indexed: 04/21/2023]
Abstract
Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension.
Collapse
Affiliation(s)
- Amir Ajoolabady
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Manlio Vinciguerra
- Liverpool Centre for Cardiovascular Science, Liverpool Johns Moore University, Liverpool, UK
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
| | - Claudio Franceschi
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Institute of Neurological Sciences of Bologna, Bologna, Italy; Department of Applied Mathematics and Laboratory of Systems Biology of Aging, Lobachevsky University, Nizhny Novgorod, Russia.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
| |
Collapse
|
41
|
Smith D, Layton A. The intrarenal renin-angiotensin system in hypertension: insights from mathematical modelling. J Math Biol 2023; 86:58. [PMID: 36952058 DOI: 10.1007/s00285-023-01891-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/14/2023] [Accepted: 02/21/2023] [Indexed: 03/24/2023]
Abstract
The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II-induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can be removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.
Collapse
Affiliation(s)
- Delaney Smith
- Department of Applied Mathematics, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada.
| | - Anita Layton
- Department of Applied Mathematics, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- Cheriton School of Computer Science, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- Department of Biology, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
- School of Pharmacy, University of Waterloo, 200 University Ave, Waterloo, ON, N2L 3G1, Canada
| |
Collapse
|
42
|
Zeng C, Armando I, Yang J, Jose PA. Dopamine Receptor D 1R and D 3R and GRK4 Interaction in Hypertension. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2023; 96:95-105. [PMID: 37009199 PMCID: PMC10052590 DOI: 10.59249/mkrr9549] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D1-like receptors (D1R and D5R) stimulate, while D2-like receptors (D2R, D3R, and D4R) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the D1R and D3R and their interaction in the natriuresis associated with volume expansion. The D1R- and D3R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D3R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D1R and D3R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D1R and D3R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.
Collapse
Affiliation(s)
- Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third
Military Medical University (Army Medical University), Chongqing, P. R.
China
| | - Ines Armando
- Division of Kidney Diseases and Hypertension,
Department of Medicine, The George Washington School of Medicine and Health
Sciences, Washington, DC, USA
| | - Jian Yang
- Department of Clinical Nutrition, The Third Affiliated
Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Pedro A. Jose
- Division of Kidney Diseases and Hypertension,
Department of Medicine, The George Washington School of Medicine and Health
Sciences, Washington, DC, USA
| |
Collapse
|
43
|
Angeli F, Zappa M, Reboldi G, Gentile G, Trapasso M, Spanevello A, Verdecchia P. The spike effect of acute respiratory syndrome coronavirus 2 and coronavirus disease 2019 vaccines on blood pressure. Eur J Intern Med 2023; 109:12-21. [PMID: 36528504 PMCID: PMC9744686 DOI: 10.1016/j.ejim.2022.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/14/2022]
Abstract
Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate. Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang1,7. Thus, the imbalance between Ang II and Ang1-7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination ("Spike Effect" similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities.
Collapse
Affiliation(s)
- Fabio Angeli
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy.
| | - Martina Zappa
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy
| | - Gianpaolo Reboldi
- Department of Medicine, and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, 06100, Italy
| | - Giorgio Gentile
- College of Medicine and Health. University of Exeter, Exeter, United Kingdom and Department of Nephrology, Royal Cornwall Hospitals NHS Trust, Truro, United Kingdom
| | - Monica Trapasso
- Dipartimento di Igiene e Prevenzione Sanitaria, PSAL, Sede Territoriale di Varese, ATS Insubria, Varese, 21100, Italy
| | - Antonio Spanevello
- Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy; Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, IRCCS Tradate, 21049, Italy
| | - Paolo Verdecchia
- Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, and Fondazione Umbra Cuore e Ipertensione-ONLUS, Perugia, 06100, Italy
| |
Collapse
|
44
|
Okuno K, Torimoto K, Cicalese SM, Preston K, Rizzo V, Hashimoto T, Coffman TM, Sparks MA, Eguchi S. Angiotensin II Type 1A Receptor Expressed in Smooth Muscle Cells is Required for Hypertensive Vascular Remodeling in Mice Infused With Angiotensin II. Hypertension 2023; 80:668-677. [PMID: 36628961 PMCID: PMC9931681 DOI: 10.1161/hypertensionaha.122.20601] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/29/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Ang II (angiotensin II) type 1 (AT1) receptors play a critical role in cardiovascular diseases such as hypertension. Rodents have 2 types of AT1 receptor (AT1A and AT1B) of which knock-in Tagln-mediated smooth muscle AT1A silencing attenuated Ang II-induced hypertension. Although vascular remodeling, a significant contributor to organ damage, occurs concurrently with hypertension in Ang II-infused mice, the contribution of smooth muscle AT1A in this process remains unexplored. Accordingly, it is hypothesized that smooth muscle AT1A receptors exclusively contribute to both medial thickening and adventitial fibrosis regardless of the presence of hypertension. METHODS About 1 µg/kg per minute Ang II was infused for 2 weeks in 2 distinct AT1A receptor silenced mice, knock-in Tagln-mediated constitutive smooth muscle AT1A receptor silenced mice, and Myh11-mediated inducible smooth muscle AT1A together with global AT1B silenced mice for evaluation of hypertensive cardiovascular remodeling. RESULTS Medial thickness, adventitial collagen deposition, and immune cell infiltration in aorta were increased in control mice but not in both smooth muscle AT1A receptor silenced mice. Coronary arterial perivascular fibrosis in response to Ang II infusion was also attenuated in both AT1A receptor silenced mice. Ang II-induced cardiac hypertrophy was attenuated in constitutive smooth muscle AT1A receptor silenced mice. However, Ang II-induced cardiac hypertrophy and hypertension were not altered in inducible smooth muscle AT1A receptor silenced mice. CONCLUSIONS Smooth muscle AT1A receptors mediate Ang II-induced vascular remodeling including medial hypertrophy and inflammatory perivascular fibrosis regardless of the presence of hypertension. Our data suggest an independent etiology of blood pressure elevation and hypertensive vascular remodeling in response to Ang II.
Collapse
Affiliation(s)
- Keisuke Okuno
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| | - Keiichi Torimoto
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| | - Stephanie M Cicalese
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| | - Kyle Preston
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| | - Victor Rizzo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| | - Tomoki Hashimoto
- Barrow Aneurysm and AVM Research Center, Departments of Neurosurgery and Neurobiology, Barrow Neurological Institute, Phoenix, AZ (T.H.)
| | - Thomas M Coffman
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC (T.M.C., M.A.S.)
- Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore (T.M.C.)
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC (T.M.C., M.A.S.)
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (K.O., K.T., S.M.C., K.P., V.R., S.E.)
| |
Collapse
|
45
|
Alswailmi FK. A Cross Talk between the Endocannabinoid System and Different Systems Involved in the Pathogenesis of Hypertensive Retinopathy. Pharmaceuticals (Basel) 2023; 16:ph16030345. [PMID: 36986445 PMCID: PMC10058254 DOI: 10.3390/ph16030345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/26/2023] Open
Abstract
The prognosis of hypertension leads to organ damage by causing nephropathy, stroke, retinopathy, and cardiomegaly. Retinopathy and blood pressure have been extensively discussed in relation to catecholamines of the autonomic nervous system (ANS) and angiotensin II of the renin–angiotensin aldosterone system (RAAS) but very little research has been conducted on the role of the ECS in the regulation of retinopathy and blood pressure. The endocannabinoid system (ECS) is a unique system in the body that can be considered as a master regulator of body functions. It encompasses the endogenous production of its cannabinoids, its degrading enzymes, and functional receptors which innervate and perform various functions in different organs of the body. Hypertensive retinopathy pathologies arise normally due to oxidative stress, ischemia, endothelium dysfunction, inflammation, and an activated renin–angiotensin system (RAS) and catecholamine which are vasoconstrictors in their biological nature. The question arises of which system or agent counterbalances the vasoconstrictors effect of noradrenaline and angiotensin II (Ang II) in normal individuals? In this review article, we discuss the role of the ECS and its contribution to the pathogenesis of hypertensive retinopathy. This review article will also examine the involvement of the RAS and the ANS in the pathogenesis of hypertensive retinopathy and the crosstalk between these three systems in hypertensive retinopathy. This review will also explain that the ECS, which is a vasodilator in its action, either independently counteracts the effect produced with the vasoconstriction of the ANS and Ang II or blocks some of the common pathways shared by the ECS, ANS, and Ang II in the regulation of eye functions and blood pressure. This article concludes that persistent control of blood pressure and normal functions of the eye are maintained either by decreasing systemic catecholamine, ang II, or by upregulation of the ECS which results in the regression of retinopathy induced by hypertension.
Collapse
Affiliation(s)
- Farhan Khashim Alswailmi
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al Batin, Hafr Al Batin 39524, Saudi Arabia
| |
Collapse
|
46
|
Tanrıverdi LH, Özhan O, Ulu A, Yıldız A, Ateş B, Vardı N, Acet HA, Parlakpinar H. Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II-induced hypertension. Fundam Clin Pharmacol 2023; 37:60-74. [PMID: 36117326 DOI: 10.1111/fcp.12829] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/16/2022] [Accepted: 09/06/2022] [Indexed: 01/27/2023]
Abstract
The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin-angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II-induced hypertension in rats. Sprague Dawley rats were subject to 4-week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 μg/kg), AVE0991 (576 μg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail-cuff plethysmography at 1, 15, and 29 days post-treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin-A (CYP-A), monocyte chemoattractant protein-1 (MCP-1), and cardiomyocyte degeneration but produced a decrease in vascular relaxation. HR, matrix metalloproteinase-2 and -9, NADPH oxidase-4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP-1 and CYP-A levels decreased in the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin-converting enzyme-2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II-induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.
Collapse
Affiliation(s)
| | - Onural Özhan
- Department of Medical Pharmacology, Faculty of Medicine, İnönü University, Malatya, Türkiye
| | - Ahmet Ulu
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Science, İnönü University, Malatya, Türkiye
| | - Azibe Yıldız
- Department of Histology and Medical Embryology, Faculty of Medicine, İnönü University, Malatya, Türkiye
| | - Burhan Ateş
- Biochemistry and Biomaterials Research Laboratory, Department of Chemistry, Faculty of Science, İnönü University, Malatya, Türkiye
| | - Nigar Vardı
- Department of Histology and Medical Embryology, Faculty of Medicine, İnönü University, Malatya, Türkiye
| | - Hacı Ahmet Acet
- Department of Medical Pharmacology, Faculty of Medicine, İnönü University, Malatya, Türkiye
| | - Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, İnönü University, Malatya, Türkiye
| |
Collapse
|
47
|
Meister ML, Najjar RS, Danh JP, Knapp D, Wanders D, Feresin RG. Berry consumption mitigates the hypertensive effects of a high-fat, high-sucrose diet via attenuation of renal and aortic AT 1R expression resulting in improved endothelium-derived NO bioavailability. J Nutr Biochem 2023; 112:109225. [PMID: 36435288 DOI: 10.1016/j.jnutbio.2022.109225] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/12/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022]
Abstract
Dysregulation of the renin-angiotensin system (RAS) is a contributor to high-fat diet-related blood pressure (BP) increases. Deleterious effects of dysregulated RAS result in an overproduction of reactive oxygen species and a decrease in endothelial nitric oxide (NO) bioavailability due to increased NADPH oxidase (NOX) expression. Dietary polyphenols have been shown to mitigate the imbalance in the redox state and protect against endothelial dysfunction induced by a high-fat diet. Thus, we aim to determine whether polyphenol-rich blackberry and raspberry, alone and in combination, attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the vascular endothelium and kidneys of mice. We show that a HFHS diet increased the expression of renal and aortic angiotensin type 1 receptor (AT1R). Further, NOX1 and NOX4 expression were increased in the kidney contributing to fibrotic damage. In human aortic endothelial cells (HAECs), palmitic acid increased the expression of NOX4, potentially driving oxidative damage in the aorta, as evidenced by increased nitrotyrosine expression. Berries reduced the expression of renal and aortic AT1R, leading to a subsequent decrease in renal NOX expression and reduced aortic oxidative stress evidenced by reduced nitrotyrosine expression. Blackberry and raspberry in combination increased the expression of NRF2 and its downstream proteins in HAECs, thereby reducing the oxidative burden to the endothelium. In combination, blackberry and raspberry also increased serum levels of NO metabolites. These findings indicate that blackberry and raspberry unique polyphenols may act synergistically to favorably modulate the abovementioned pathways and attenuate HFHS diet-induced increases in BP.
Collapse
Affiliation(s)
- Maureen L Meister
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Rami S Najjar
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Jessica P Danh
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Denise Knapp
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Desiree Wanders
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Rafaela G Feresin
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA.
| |
Collapse
|
48
|
Renal sympathetic activity: A key modulator of pressure natriuresis in hypertension. Biochem Pharmacol 2023; 208:115386. [PMID: 36535529 DOI: 10.1016/j.bcp.2022.115386] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Hypertension is a complex disorder ensuing necessarily from alterations in the pressure-natriuresis relationship, the main determinant of long-term control of blood pressure. This mechanism sets natriuresis to the level of blood pressure, so that increasing pressure translates into higher osmotically driven diuresis to reduce volemia and control blood pressure. External factors affecting the renal handling of sodium regulate the pressure-natriuresis relationship so that more or less natriuresis is attained for each level of blood pressure. Hypertension can thus only develop following primary alterations in the pressure to natriuresis balance, or by abnormal activity of the regulation network. On the other hand, increased sympathetic tone is a very frequent finding in most forms of hypertension, long regarded as a key element in the pathophysiological scenario. In this article, we critically analyze the interplay of the renal component of the sympathetic nervous system and the pressure-natriuresis mechanism in the development of hypertension. A special focus is placed on discussing recent findings supporting a role of baroreceptors as a component, along with the afference of reno-renal reflex, of the input to the nucleus tractus solitarius, the central structure governing the long-term regulation of renal sympathetic efferent tone.
Collapse
|
49
|
Altara R, Booz G. Central role for BRAF in cardiac hypertrophy: rethinking the pathological-physiological divide. Clin Sci (Lond) 2023; 137:143-148. [PMID: 36651286 PMCID: PMC9873497 DOI: 10.1042/cs20220776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/23/2022] [Accepted: 01/05/2023] [Indexed: 01/19/2023]
Abstract
The RAF/MEK/ERK1/2 signaling cascade has been implicated in pathological cardiac hypertrophy downstream of some Gq-coupled receptors. The RAF family of kinases consists of three isoforms (ARAF, BRAF, and CRAF) and until recently most studies on this signaling pathway in the heart have focused on RAF1 (CRAF). In a recent issue of Clinical Science, Alharbi et al. utilized an inducible cardiac myocyte targeted knockout mouse model to define the role of BRAF in pathological versus physiological hypertrophy using angiotensin II and phenylephrine (PE) infusion, respectively. They reported that loss of BRAF attenuated both pathological cardiac hypertrophy and interstitial fibrosis. BRAF knockout decreased cardiac function with PE in male mice and enhanced both interstitial and perivascular cardiac fibrosis but had no effect on hypertrophy. In contrast, loss of BRAF attenuated physiological hypertrophy in female mice but had no effect on fibrosis or contractility. These observations extend those previously made by this group assessing the consequences of expressing an inducible activating mutant of BRAF in the heart and the benefit of enhancing RAF/MEK/ERK1/2 signaling by exploiting the 'RAF paradox'. Additional studies are needed to better define the role of BRAF under conditions reflective of chronic stress on the heart due to the biomechanical stimulation exerted by hypertension. In addition, the role of BRAF and its activation in overt heart failure remains to be established. Nevertheless, the new findings highlight the potential importance of additional signaling events, perhaps related to RAF1 or ERK1/2 activation, in shaping BRAF signaling in a sex- and context-dependent manner.
Collapse
Affiliation(s)
- Raffaele Altara
- Department of Pathology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A
- Department of Anatomy and Embryology, Maastricht University, Maastricht, The Netherlands
| | - George W. Booz
- Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A
- Correspondence: George W. Booz ()
| |
Collapse
|
50
|
Renal angiotensin I-converting enzyme-deficient mice are protected against aristolochic acid nephropathy. Pflugers Arch 2023; 475:391-403. [PMID: 36520238 PMCID: PMC9908662 DOI: 10.1007/s00424-022-02779-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
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.
Collapse
|