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1
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Rahman MM, Rahman A, Nishiyama A. Potential renoprotective effects and possible underlying mechanisms of angiotensin receptor-neprilysin inhibitors in cardiorenal syndrome. Front Med (Lausanne) 2025; 11:1451450. [PMID: 39839622 PMCID: PMC11747313 DOI: 10.3389/fmed.2024.1451450] [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: 06/19/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Angiotensin receptor-neprilysin inhibitors (ARNIs) represent a novel class of medications characterized by their dual action on major cardiorenal regulators, specifically the renin-angiotensin system (RAS) and the natriuretic peptide (NP) system. Sacubitril/valsartan, a pioneering ARNI, has demonstrated strong antihypertensive effect as well as superior efficacy in preserving renal function compared to RAS inhibitors in heart failure patients with reduced ejection fraction. Here, we gathered evidence on the impact of sacubitril/valsartan on the preservation of kidney function in patients with cardiorenal syndrome (CRS). In particular, we present a comprehensive summary of the latest advancements and findings from clinical trials, studies, and meta-analyses on the impact of ARNIs in maintaining or improving renal function. We also discussed the pre-clinical evidence supporting the use of sacubitril/valsartan for improving renal function, along with the underlying molecular mechanisms in animal models mimicking various clinical scenarios. Altogether, the analysis of published data from both pre-clinical and clinical studies provides substantial support for the usefulness of ARNIs in enhancing renal protection in subjects with CRS.
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Affiliation(s)
- Md Moshiur Rahman
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
- Department of Pharmacology and Toxicology, Faculty of Animal Science and Veterinary Medicine, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh
| | - Asadur Rahman
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
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2
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Rodrigues AF, Domenig O, Poglitsch M, Bader M, Danser AJ. Angiotensin-(1-12): Does It Exist? A Critical Evaluation in Humans, Rats, and Mice. Hypertension 2024; 81:1776-1784. [PMID: 38716648 PMCID: PMC11251504 DOI: 10.1161/hypertensionaha.124.22856] [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: 02/05/2024] [Accepted: 04/22/2024] [Indexed: 07/18/2024]
Abstract
BACKGROUND Angiotensin-(1-12), measured by a self-developed, polyclonal antibody-based radioimmunoassay, has been suggested to act as an alternative precursor of angiotensin II. A more reliable detection method would be liquid chromatography-tandem mass spectrometry. METHODS We set up the quantification of human and murine angiotensin-(1-12) by liquid chromatography-tandem mass spectrometry and then used this method to measure angiotensin-(1-12) in human, rat, and mouse blood samples, as well as in mouse brain, mouse kidney, and rat heart. We also verified ex vivo angiotensin-(1-12) generation and metabolism in human blood samples incubated at 37 °C. RESULTS Stabilization of blood in guanidine hydrochloride was chosen for sample collection since this allowed full recovery of spiked angiotensin-(1-12). Angiotensin-(1-12) was undetectable in human blood samples when incubating nonstabilized plasma at 37 °C, while angiotensin-(1-12) added to nonstabilized human plasma disappeared within 10 minutes. Stabilized human blood samples contained angiotensin II, while angiotensin-(1-12) was undetectable. Blood, hearts, and kidneys, but not brains, of wild-type mice and rats contained detectable levels of angiotensin II, while angiotensin-(1-12) was undetectable. In renin knockout mice, all angiotensins, including angiotensin-(1-12), were undetectable at all sites, despite a 50% rise in angiotensinogen. Angiotensin-(1-12) metabolism in human blood plasma was not affected by renin inhibition. Yet, blockade of angiotensin-converting enzyme and aminopeptidase A, but not of chymase, neutral endopeptidase, or prolyl oligopeptidase, prolonged the half-life of angiotensin-(1-12), and angiotensin-converting enzyme inhibition prevented the formation of angiotensin II. CONCLUSIONS We were unable to detect intact angiotensin-(1-12) in humans, rats, and mice, either in blood or tissue, suggesting that this metabolite is an unlikely source of endogenous angiotensins.
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Affiliation(s)
- André F. Rodrigues
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (A.F.R., M.B.)
- German Center for Cardiovascular Research, Berlin, Germany (A.F.R., M.B.)
| | | | | | - Michael Bader
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (A.F.R., M.B.)
- German Center for Cardiovascular Research, Berlin, Germany (A.F.R., M.B.)
- Charité Universitätsmedizin Berlin, Germany (M.B.)
- Institute for Biology, University of Lübeck, Germany (M.B.)
| | - A.H. Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands (A.H.J.D.)
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3
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Liu Y, Lu CY, Zheng Y, Zhang YM, Qian LL, Li KL, Tse G, Wang RX, Liu T. Role of angiotensin receptor-neprilysin inhibitor in diabetic complications. World J Diabetes 2024; 15:867-875. [PMID: 38766431 PMCID: PMC11099356 DOI: 10.4239/wjd.v15.i5.867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/31/2023] [Accepted: 03/25/2024] [Indexed: 05/10/2024] Open
Abstract
Diabetes mellitus is a prevalent disorder with multi-system manifestations, causing a significant burden in terms of disability and deaths globally. Angio-tensin receptor-neprilysin inhibitor (ARNI) belongs to a class of medications for treating heart failure, with the benefits of reducing hospitalization rates and mortality. This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications, discussing possible physiological and molecular mechanisms, with insights for future applications.
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Affiliation(s)
- Ying Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Cun-Yu Lu
- Department of Cardiology, Xuzhou No. 1 Peoples Hospital, Xuzhou 221005, Jiangsu Province, China
| | - Yi Zheng
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yu-Min Zhang
- Department of Cardiology, Wuxi 9th People’s Hospital Affiliated to Soochow University, Wuxi 214062, Jiangsu Province, China
| | - Ling-Ling Qian
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Ku-Lin Li
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Gary Tse
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
- School of Nursing and Health Studies, Metropolitan University, Hong Kong 999077, China
- Kent and Medway Medical School, Kent CT2 7NT, Canterbury, United Kingdom
| | - Ru-Xing Wang
- Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
| | - Tong Liu
- Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, China
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4
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Cruz-López EO, Ye D, Stolk DG, Clahsen-van Groningen MC, van Veghel R, Garrelds IM, Poglitsch M, Domenig O, Alipour Symakani RS, Merkus D, Verdonk K, Jan Danser AH. Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects. J Hypertens 2024; 42:883-892. [PMID: 38088400 DOI: 10.1097/hjh.0000000000003633] [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: 04/05/2024]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats. METHODS Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry. RESULTS Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1-7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1-7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney. CONCLUSION RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1-7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.
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Affiliation(s)
- Edwyn O Cruz-López
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | - Dien Ye
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | - Daniel G Stolk
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | | | - Richard van Veghel
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | - Ingrid M Garrelds
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | | | | | - Rahi S Alipour Symakani
- Division of Experimental Cardiology, Department of Cardiology
- Department of Cardiothoracic Surgery
- Division of Pediatric Cardiology, Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Center, The Netherlands
| | - Daphne Merkus
- Division of Experimental Cardiology, Department of Cardiology
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, LMU University Hospital, LMU Munich
- Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377 Munich, Germany
| | - Koen Verdonk
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
| | - A H Jan Danser
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine
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5
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Schellinger IN, Dannert A, Hoffmann A, Chodisetti G, Mattern K, Petzold A, Klöting N, Schuster A, Wagenhäuser MU, Emrich F, Stumvoll M, Hasenfuß G, Raaz U. Angiotensin Receptor-Neprilysin Inhibition (Sacubitril/Valsartan) Reduces Structural Arterial Stiffness in Middle-Aged Mice. J Am Heart Assoc 2024; 13:e032641. [PMID: 38348796 PMCID: PMC11010079 DOI: 10.1161/jaha.123.032641] [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: 10/18/2023] [Accepted: 01/09/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age-related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age-related arterial fibrotic remodeling and stiffening in 1-year-old mice. METHODS AND RESULTS Treatment of in 1-year-old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse-wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. CONCLUSIONS This study provides preclinical mechanistic evidence indicating that ARNI-based interventions may counteract age-related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.
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Affiliation(s)
- Isabel N. Schellinger
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
- German Center for Cardiovascular Research (DZHK) e.V. Partner site GöttingenGöttingenGermany
- Department for Endocrinology, Nephrology and RheumatologyUniversity Medical Center Leipzig, University of LeipzigLeipzigGermany
| | - Angelika Dannert
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
| | - Annet Hoffmann
- Department for Endocrinology, Nephrology and RheumatologyUniversity Medical Center Leipzig, University of LeipzigLeipzigGermany
| | - Giriprakash Chodisetti
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
| | - Karin Mattern
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
| | - Anne Petzold
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
| | - Nora Klöting
- Department for Endocrinology, Nephrology and RheumatologyUniversity Medical Center Leipzig, University of LeipzigLeipzigGermany
| | - Andreas Schuster
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
- German Center for Cardiovascular Research (DZHK) e.V. Partner site GöttingenGöttingenGermany
| | - Markus U. Wagenhäuser
- Department of Vascular and Endovascular SurgeryUniversity Hospital Düsseldorf, Heinrich‐Heine‐UniversityDüsseldorfGermany
| | - Fabian Emrich
- Department of Cardiothoracic and Vascular SurgeryGoethe University Hospital FrankfurtFrankfurtGermany
| | - Michael Stumvoll
- Department for Endocrinology, Nephrology and RheumatologyUniversity Medical Center Leipzig, University of LeipzigLeipzigGermany
| | - Gerd Hasenfuß
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
- German Center for Cardiovascular Research (DZHK) e.V. Partner site GöttingenGöttingenGermany
| | - Uwe Raaz
- Department of Cardiology and PneumologyHeart Center at the University Medical Center GöttingenGöttingenGermany
- German Center for Cardiovascular Research (DZHK) e.V. Partner site GöttingenGöttingenGermany
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6
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Zhang M, Zou Y, Li Y, Wang H, Sun W, Liu B. The history and mystery of sacubitril/valsartan: From clinical trial to the real world. Front Cardiovasc Med 2023; 10:1102521. [PMID: 37057101 PMCID: PMC10086241 DOI: 10.3389/fcvm.2023.1102521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Heart failure is a serious threat to human health, with morbidity and mortality rates increasing despite the existence of multiple treatment options. Therefore, it is necessary to identify new therapeutic targets for this disease. Sacubitril/valsartan is a supramolecular sodium salt complex of the enkephalinase inhibitor prodrug sacubitril and the angiotensin receptor blocker valsartan. Its combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects. Clinical evidence suggests that sacubitril/valsartan is superior to conventional renin-angiotensin-aldosterone inhibitor therapy for patients with reduced ejection fraction heart failure who can tolerate angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The therapy reduces the risk of heart failure hospitalization, cardiovascular mortality, and all-cause mortality and has a better safety and tolerability record. This review describes the potential pathophysiological mechanisms of cardiomyocyte injury amelioration by sacubitril/valsartan. We explore the protective effects of sacubitril/valsartan and outline the therapeutic value in patients with heart failure by summarizing the results of recent large clinical trials. Furthermore, a preliminary outlook shows that sacubitril/valsartan may be effective at treating other diseases, and provides some exploratory observations that lay the foundation for future studies on this drug.
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Affiliation(s)
| | | | | | | | - Wei Sun
- Correspondence: Wei Sun Bin Liu
| | - Bin Liu
- Correspondence: Wei Sun Bin Liu
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7
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Mohammed Abdulsalam T, Hasanin AH, Hussein Mohamed R, Khairy E, Mahmoud D, Habib E, Badawy AES. Angiotensin receptor-neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury. Fundam Clin Pharmacol 2023; 37:31-43. [PMID: 35830481 DOI: 10.1111/fcp.12818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/20/2022] [Accepted: 07/11/2022] [Indexed: 01/25/2023]
Abstract
Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor-neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia-reperfusion I/R, (III) TH/IRB + IR (0.1/5 mg/kg), (IV) TH/IRB + IR (0.1/10 mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dtmax ), and cardiac levels of creatine kinase-MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10 mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.
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Affiliation(s)
| | - Amany H Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Reham Hussein Mohamed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman Khairy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Dalia Mahmoud
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Eman Habib
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed El Sayed Badawy
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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8
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Cruz-López EO, Ren L, Uijl E, Clahsen-van Groningen MC, van Veghel R, Garrelds IM, Domenig O, Poglitsch M, Zlatev I, Rooney T, Kasper A, Nioi P, Foster D, Danser AHJ. Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes. Br J Pharmacol 2023; 180:80-93. [PMID: 36106615 PMCID: PMC10091936 DOI: 10.1111/bph.15955] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/23/2022] [Accepted: 08/30/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. EXPERIMENTAL APPROACH To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT1 antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. KEY RESULTS MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. CONCLUSION AND IMPLICATIONS Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.
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Affiliation(s)
- Edwyn O Cruz-López
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Liwei Ren
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.,Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Estrellita Uijl
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.,Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Marian C Clahsen-van Groningen
- Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.,Institute of Experimental Medicine and Systems Biology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Richard van Veghel
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Ingrid M Garrelds
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - Ivan Zlatev
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | | | - Anne Kasper
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Paul Nioi
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Don Foster
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - A H Jan Danser
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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9
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Cruz-López EO, Ye D, Wu C, Lu HS, Uijl E, Mirabito Colafella KM, Danser AHJ. Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease. Hypertension 2022; 79:2115-2126. [PMID: 35904033 PMCID: PMC9444253 DOI: 10.1161/hypertensionaha.122.18731] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.
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Affiliation(s)
- Edwyn O Cruz-López
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (E.O.C.L., D.Y., E.U., A.H.J.D.)
| | - Dien Ye
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (E.O.C.L., D.Y., E.U., A.H.J.D.)
| | - Congqing Wu
- Saha Cardiovascular Research Center (C.W., H.S.L.), University of Kentucky.,Department of Surgery (C.W.), University of Kentucky
| | - Hong S Lu
- Saha Cardiovascular Research Center (C.W., H.S.L.), University of Kentucky.,Department of Physiology (H.S.L.), University of Kentucky
| | - Estrellita Uijl
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (E.O.C.L., D.Y., E.U., A.H.J.D.)
| | | | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands (E.O.C.L., D.Y., E.U., A.H.J.D.)
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10
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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11
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Jia R, Zhang X, Xu Y, Zheng Z, Jiang L, Zhang X, Sun C, Wu X, Li S, Raj A, Sun D. Effect of Sacubitril/Valsartan on renal function in patients with chronic kidney disease and heart failure with preserved ejection fraction: A real-world 12-week study. Eur J Pharmacol 2022; 928:175053. [PMID: 35709921 DOI: 10.1016/j.ejphar.2022.175053] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 11/03/2022]
Abstract
Patients with chronic kidney disease (CKD) are often complicated with heart failure with preserved ejection fraction (HFpEF). However, several drugs, including angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB), have not shown apparent benefits in terms of morbidity and mortality of HFpEF. PARAMOUNT and other studies have shown the potential benefits of Sacubitril/Valsartan on patients with HFpEF, but its effects on renal function and the effect of low-dose Sacubitril/Valsartan in actual clinical conditions have not been thoroughly evaluated. In our longitudinal and observational research, 353 patients were followed up for 12 weeks. We evaluated renal function [urinary protein, serum creatinine and estimated glomerular filtration rate (eGFR)] and cardiac function [NT-proBNP (brain natriuretic peptide), New York Heart Association (NYHA) classification, left ventricular ejection fraction (LVEF), left atrial width and left ventricular end-diastolic width] at baseline and during follow-up. Worsening renal function (WRF) was defined as an increased serum creatinine≥26.5umol/L or decreased eGFR≥20%. The decline of eGFR in the Sacubitril/Valsartan group was slower than that in the control group (p = 0.021). The outcome of proteinuria in the ACEI/ARB group was significantly better than that in the Sacubitril/Valsartan group (p = 0.001). In terms of echocardiogram, the average left atrial width in Sacubitril/Valsartan group decreased by 1.38 ± 3.02 mm, which was significantly lower than that in the ACEI/ARB group (p = 0.02). The increase of urine protein class in the ACEI/ARB group increased the risk of WRF with statistical significance (OR = 2.36, 95%CI 1.01-5.49, p = 0.047), but no statistical significance was found in all the patients or Sacubitril/Valsartan group. In conclusion, Sacubitril/Valsartan could more effectively slow down renal function decline and reverse myocardial remodeling in patients with CKD and HFpEF than ACEI/ARB, even at low doses, though its protective effect on urinary protein is not as good as that of ACEI/ARB.
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Affiliation(s)
- Ruoyu Jia
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xuejie Zhang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yizhou Xu
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Zhifang Zheng
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Luhua Jiang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xin Zhang
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Institute of Nephrology, Xuzhou Medical University, Xuzhou, 221002, China
| | - Chen Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xin Wu
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Shulin Li
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Ashok Raj
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Dong Sun
- Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Institute of Nephrology, Xuzhou Medical University, Xuzhou, 221002, China.
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12
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Xu X, Li Y, Shi S, Lv J, Wang Y, Zheng H, Mao X, Wu H, Zhang B, Song Q. The Application of Angiotensin Receptor Neprilysin Inhibitor in Cardiovascular Diseases: A Bibliometric Review From 2000 to 2022. Front Cardiovasc Med 2022; 9:899235. [PMID: 35600466 PMCID: PMC9114353 DOI: 10.3389/fcvm.2022.899235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/19/2022] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular disease (CVD) has become a huge challenge for the global public health system due to its high morbidity, mortality and severe economic burden. In recent years, angiotensin receptor neprilysin inhibitor (ARNI), a new class of drugs, has shown good therapeutic effects on CVD patients in several clinical studies, reducing the morbidity and mortality of CVD patients. In this study, we retrieved publications on ARNI research in the cardiovascular field from the Web of Science core collection and analyzed the annual output, spatial and temporal distribution, institutions and authors, core journals, keywords and co-cited literature based on CiteSpace. As a result, 604 publications were retrieved, and the number of annual publications generally increased year by year, with the largest number of articles. The analysis of the co-occurrence of output countries and authors showed that a few developed countries such as the United States, Canada, and United Kingdom are the most active in this field, forming academic groups represented by John Joseph Valentine McMurray and Scott D. Solomon, and New England Journal of Medicine, Cirulation, and Journal of the American College of Cardiology are the most popular journals in the field, with research hotspots focused on ARNI in the treatment of total ejection fraction heart failure, hypertension and its target organ damage, with the potential for future benefit throughout the cardiovascular event chain as research progresses. This study reveals the prospective application of ARNI in the cardiovascular field and the research hotspots, providing broader and deeper guidance for its use in the clinic, which is beneficial to improve the treatment and prognosis of CVD patients.
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Affiliation(s)
- Xia Xu
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yumeng Li
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shuqing Shi
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayu Lv
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yajiao Wang
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Haoran Zheng
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xinxin Mao
- College of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huaqin Wu
- Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Huaqin Wu, ;
| | - Bingxuan Zhang
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Bingxuan Zhang, ;
| | - Qingqiao Song
- Department of General Internal Medicine, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Qingqiao Song, ;
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13
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What the near Future Holds for Sacubitril/Valsartan: A Summary of Major Ongoing Studies. J Cardiovasc Dev Dis 2022; 9:jcdd9020054. [PMID: 35200707 PMCID: PMC8875386 DOI: 10.3390/jcdd9020054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 12/11/2022] Open
Abstract
Early research on neprilysin inhibition showed that sacubitril/valsartan, a combination of the valsartan and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF study in 2014. Therefore, for patients with HFrEF, worldwide recommendations have been reformed to include sacubitril/valsartan. In addition, sacubitril/valsartan has been investigated in other cardiovascular disease states, such as patients with heart failure and preserved ejection fraction (HFpEF) and following myocardial infarction (MI) events. In February 2021, the FDA expanded the indication use of sacubitril/valsartan to include the HFpEF patient population based on the results of the PARAGON-HF trial. However, randomized clinical trials post-MI did not show promising results. Sacubitril/valsartan is currently being investigated in many other cardiovascular and non-cardiovascular conditions. This review aims to shed light and summarize the ongoing sacubitril/valsartan registered studies on the United States National Library of Medicine clinical trials registry.
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14
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Zhang X, Zhou Y, Ma R. Potential effects and application prospect of angiotensin receptor-neprilysin inhibitor in diabetic kidney disease. J Diabetes Complications 2022; 36:108056. [PMID: 34893426 DOI: 10.1016/j.jdiacomp.2021.108056] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/21/2021] [Accepted: 09/25/2021] [Indexed: 12/18/2022]
Abstract
Diabetic kidney disease (DKD) is one of the main causes of end-stage renal disease (ESRD) and all-cause mortality in diabetic patients, despite the extensive use of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Angiotensin receptor-neprilysin inhibitor (ARNI), combining ARB and neutral endopeptidase inhibitor (NEPI), is likely to have potential favorable effects in DKD. This review summarizes existing preclinical and clinical studies on mechanism of ARNI and its potential effects on DKD. In preclinical studies, ARNI manifested its renoprotective effects by improving natriuresis, ameliorating inflammation, oxidative stress and renal dysfunction, and slowing down glomerulosclerosis and tubulointerstitial injury of kidney, but its effect on proteinuria is still controversial. Beneficial effects of ARNI on blood glucose regulation and glycometabolism have also been reported. There are no clinical studies of ARNI that specifically focus on DKD patients so far. ARNI has application potential in DKD, but there still need clinical studies that focus on DKD patients to determine its effectiveness, safety and underlying mechanism.
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Affiliation(s)
- Xingjian Zhang
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yan Zhou
- Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Ruixia Ma
- Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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15
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AlSiraj Y, Thatcher SE, Liang CL, Ali H, Ensor M, Cassis LA. Therapeutic Assessment of Combination Therapy with a Neprilysin Inhibitor and Angiotensin Type 1 Receptor Antagonist on Angiotensin II-Induced Atherosclerosis, Abdominal Aortic Aneurysms, and Hypertension. J Pharmacol Exp Ther 2021; 377:326-335. [PMID: 33707301 PMCID: PMC8140395 DOI: 10.1124/jpet.121.000525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/05/2021] [Indexed: 12/21/2022] Open
Abstract
Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis, and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system. In this study, we examined NEP inhibition (with sacubitril) and AT1R antagonism (with valsartan) alone or in combination on AngII-induced hypertension, atherosclerosis, or AAAs in male low-density lipoprotein receptor-deficient mice. Preliminary studies assessed drug delivery via osmotic minipumps for simultaneous release of sacubitril and/or valsartan with AngII over 28 days. Mice were infused with AngII (1000 ng/kg per minute) in the absence (vehicle) or presence of sacubitril (1, 6, or 9 mg/kg per day), valsartan (0.3, 0.5, 1, 6, or 20 mg/kg per day), or the combination thereof (1 and 0.3, or 9 or 0.5 mg/kg per day of sacubitril and valsartan, respectively). Plasma AngII and renin concentrations increased 4-fold at higher valsartan doses, indicative of removal of AngII negative feedback on renin. Sacubitril doubled plasma AngII concentrations at lower doses (1 mg/kg per day). Valsartan dose-dependently decreased systolic blood pressure, aortic atherosclerosis, and AAAs of AngII-infused mice, whereas sacubitril had no effect on atherosclerosis or AAAs but reduced blood pressure of AngII-infused mice. Combination therapy with sacubitril and valsartan did not provide additive benefits. These results suggest limited effects of combination therapy with NEP inhibition and AT1R antagonism against AngII-induced hypertension, atherosclerosis, or AAAs. SIGNIFICANCE STATEMENT: The combination of valsartan (angiotensin type 1 receptor antagonist) and sacubitril (neprilysin inhibitor) did not provide benefit above valsartan alone on AngII-induced hypertension, atherosclerosis, or abdominal aortic aneurysms in low-density lipoprotein receptor-deficient male mice. These results do not support this drug combination in therapy of these AngII-induced cardiovascular diseases.
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Affiliation(s)
- Yasir AlSiraj
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Sean E Thatcher
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Ching Ling Liang
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Heba Ali
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Mark Ensor
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Lisa A Cassis
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
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16
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Choi MR, Fernández BE. Protective Renal Effects of Atrial Natriuretic Peptide: Where Are We Now? Front Physiol 2021; 12:680213. [PMID: 34135773 PMCID: PMC8202499 DOI: 10.3389/fphys.2021.680213] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Atrial natriuretic peptide belongs to the family of natriuretic peptides, a system with natriuretic, diuretic, and vasodilator effects that opposes to renin-angiotensin system. In addition to its classic actions, atrial natriuretic peptide exerts a nephroprotective effect given its antioxidant and anti-inflammatory properties, turning it as a beneficial agent against acute and chronic kidney diseases. This minireview describes the most relevant aspects of atrial natriuretic peptide in the kidney, including its renal synthesis, physiological actions through specific receptors, the importance of its metabolism, and its potential use in different pathological scenarios.
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Affiliation(s)
- Marcelo Roberto Choi
- Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina.,Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Cátedra de Anatomía e Histología, Universidad de Buenos Aires, Buenos Aires, Argentina.,Instituto Universitario de Ciencias de la Salud, Fundación H.A. Barceló, Buenos Aires, Argentina
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17
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Angiotensin-neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury. J Hypertens 2021; 38:755-764. [PMID: 31790054 DOI: 10.1097/hjh.0000000000002326] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss. METHODS To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry. RESULTS Sacubitril/valsartan lowered mean arterial pressure by -50 ± 4 mmHg and valsartan by -43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration. CONCLUSION Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity.
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18
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Spannella F, Giulietti F, Filipponi A, Sarzani R. Effect of sacubitril/valsartan on renal function: a systematic review and meta-analysis of randomized controlled trials. ESC Heart Fail 2020; 7:3487-3496. [PMID: 32960491 PMCID: PMC7754726 DOI: 10.1002/ehf2.13002] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/15/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
A worsening renal function is prevalent among patients with cardiovascular disease, especially heart failure (HF). Sacubitril/valsartan appears to prevent worsening of renal function and progression of chronic kidney disease (CKD) as compared with renin-angiotensin system (RAS) inhibitors alone in HF patients. It is unclear whether these advantages are present in HF patients only, or can be extended to other categories of patients, in which this drug was studied. We performed a systematic review and meta-analysis to assess the consistency of effect size regarding renal outcome across randomized controlled trials (RCTs) that compared sacubitril/valsartan with RAS inhibitors in patients with or without HF. We searched Medline (PubMed), Scopus, and Thomson Reuters Web of Science databases until June 2020. We took into account RCTs that compared sacubitril/valsartan with a RAS inhibitor and reported data regarding renal function. We used random-effects models to obtain summary odds ratio (OR) with 95% confidence interval (CI). We extracted hazard ratios for renal outcomes, glomerular filtration rate slopes or rates of renal adverse events. Sensitivity analyses were performed by moderator analysis and random-effects meta-regression. The search revealed 10 RCTs (published between 2012 and 2019) on 16 456 subjects. Sacubitril/valsartan resulted in a lower risk of renal dysfunction as compared with RAS inhibitors alone [k = 10; pooled OR = 0.70 (95% CI 0.57-0.85); P < 0.001], with a moderate inconsistency between studies [Q(9) = 15.18; P = 0.086; I2 = 40.73%]. A stronger association was found in studies including older patients (k = 10; β = -0.047730; P = 0.020) or HF patients with preserved ejection fraction [pooled OR = 0.53 (0.41-0.68) vs. 0.76 (0.57-1.01) for studies on HF patients with reduced ejection fraction; P for comparison = 0.065]. The effect size did not change with different comparators (angiotensin-converting enzyme inhibitors vs. angiotensin II type 1 receptor blockers, P = 0.279). No significant association was found when the analysis was restricted to studies on non-HF patients [k = 3; pooled OR = 0.86 (0.61-1.22); P = 0.403] and studies with high risk of bias [k = 3; pooled OR = 0.34 (0.08-1.44); P = 0.143]. Our findings support the role of sacubitril/valsartan on preservation of renal function, especially in older patients and HF patients with preserved ejection fraction. However, evidence is currently limited to HF patients, while the renal outcome of sacubitril/valsartan therapy outside the HF setting needs to be further investigated.
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Affiliation(s)
- Francesco Spannella
- Internal Medicine and GeriatricsIRCCS INRCAVia della Montagnola 81AnconaItaly
- Department of Clinical and Molecular SciencesUniversity ‘Politecnica delle Marche’Via Tronto 10/aAnconaItaly
| | - Federico Giulietti
- Internal Medicine and GeriatricsIRCCS INRCAVia della Montagnola 81AnconaItaly
- Department of Clinical and Molecular SciencesUniversity ‘Politecnica delle Marche’Via Tronto 10/aAnconaItaly
| | - Andrea Filipponi
- Internal Medicine and GeriatricsIRCCS INRCAVia della Montagnola 81AnconaItaly
- Department of Clinical and Molecular SciencesUniversity ‘Politecnica delle Marche’Via Tronto 10/aAnconaItaly
| | - Riccardo Sarzani
- Internal Medicine and GeriatricsIRCCS INRCAVia della Montagnola 81AnconaItaly
- Department of Clinical and Molecular SciencesUniversity ‘Politecnica delle Marche’Via Tronto 10/aAnconaItaly
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19
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Alleviation of salt-induced exacerbation of cardiac, renal, and visceral fat pathology in rats with metabolic syndrome by surgical removal of subcutaneous fat. Nutr Diabetes 2020; 10:28. [PMID: 32778644 PMCID: PMC7417575 DOI: 10.1038/s41387-020-00132-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Evidence suggests that visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) should be considered as distinct types of white fat. Although VAT plays a key role in metabolic syndrome (MetS), the role of subcutaneous adipose tissue (SAT) has been unclear. DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of MetS, develop adipocyte hypertrophy and inflammation to similar extents in SAT and VAT. We have now investigated the effects of salt loading and SAT removal on cardiac, renal, and VAT pathology in DS/obese rats. METHODS DS/obese rats were subjected to surgical removal of inguinal SAT or sham surgery at 8 weeks of age. They were provided with a 0.3% NaCl solution as drinking water or water alone for 4 weeks from 9 weeks of age. RESULTS Salt loading exacerbated hypertension, insulin resistance, as well as left ventricular (LV) hypertrophy, inflammation, fibrosis, and diastolic dysfunction in DS/obese rats. It also reduced both SAT and VAT mass but aggravated inflammation only in VAT. Although SAT removal did not affect LV hypertrophy in salt-loaded DS/obese rats, it attenuated hypertension, insulin resistance, and LV injury as well as restored fat mass and alleviated inflammation and the downregulation of adiponectin gene expression in VAT. In addition, whereas salt loading worsened renal injury as well as upregulated the expression of renin-angiotensin-aldosterone system-related genes in the kidney, these effects were suppressed by removal of SAT. CONCLUSIONS SAT removal attenuated salt-induced exacerbation of MetS and LV and renal pathology in DS/obese rats. These beneficial effects of SAT removal are likely attributable, at least in part, to inhibition of both VAT and systemic inflammation.
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20
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Polina I, Domondon M, Fox R, Sudarikova AV, Troncoso M, Vasileva VY, Kashyrina Y, Gooz MB, Schibalski RS, DeLeon-Pennell KY, Fitzgibbon WR, Ilatovskaya DV. Differential effects of low-dose sacubitril and/or valsartan on renal disease in salt-sensitive hypertension. Am J Physiol Renal Physiol 2020; 319:F63-F75. [PMID: 32463726 PMCID: PMC7468826 DOI: 10.1152/ajprenal.00125.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/15/2022] Open
Abstract
Diuretics and renin-angiotensin system blockers are often insufficient to control the blood pressure (BP) in salt-sensitive (SS) subjects. Abundant data support the proposal that the level of atrial natriuretic peptide may correlate with the pathogenesis of SS hypertension. We hypothesized here that increasing atrial natriuretic peptide levels with sacubitril, combined with renin-angiotensin system blockage by valsartan, can be beneficial for alleviation of renal damage in a model of SS hypertension, the Dahl SS rat. To induce a BP increase, rats were challenged with a high-salt 4% NaCl diet for 21 days, and chronic administration of vehicle or low-dose sacubitril and/or valsartan (75 μg/day each) was performed. Urine flow, Na+ excretion, and water consumption were increased on the high-salt diet compared with the starting point (0.4% NaCl) in all groups but remained similar among the groups at the end of the protocol. Upon salt challenge, we observed a mild decrease in systolic BP and urinary neutrophil gelatinase-associated lipocalin levels (indicative of alleviated tubular damage) in the valsartan-treated groups. Sacubitril, as well as sacubitril/valsartan, attenuated the glomerular filtration rate decline induced by salt. Alleviation of protein cast formation and lower renal medullary fibrosis were observed in the sacubitril/valsartan- and valsartan-treated groups, but not when sacubitril alone was administered. Interestingly, proteinuria was mildly mitigated only in rats that received sacubitril/valsartan. Further studies of the effects of sacubitril/valsartan in the setting of SS hypertension, perhaps involving a higher dose of the drug, are warranted to determine if it can interfere with the progression of the disease.
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Affiliation(s)
- Iuliia Polina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Mark Domondon
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Rebecca Fox
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Anastasia V Sudarikova
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Miguel Troncoso
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Valeriia Y Vasileva
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Yuliia Kashyrina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Monika Beck Gooz
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Ryan S Schibalski
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Kristine Y DeLeon-Pennell
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
| | - Wayne R Fitzgibbon
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Daria V Ilatovskaya
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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21
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Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study. Eur J Pharmacol 2020; 882:173295. [PMID: 32593664 DOI: 10.1016/j.ejphar.2020.173295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 06/07/2020] [Accepted: 06/17/2020] [Indexed: 11/20/2022]
Abstract
Ventricular arrhythmias are considered as a major risk of sudden cardiac death. This study was designed to investigate the potential effects of angiotensin receptor neprilysin inhibitor; thiorphan/irbesartan (TH/IRB) combination therapy on myocardial ischemic-reperfusion (I/R)-induced arrhythmia. Fifty male Wistar rats were divided into 5 groups; (I, II): Sham, I/R both received DMSO intraperitoneally before the procedure. (III, IV, V): TH/IRB + IR (0.1/5 mg/kg, 0.1/10 mg/kg and 0.1/15 mg/kg). The drugs were injected intraperitoneally 15 min before I/R induction. Electrocardiograms changes, mean arterial blood pressure, incidence of ventricular tachycardia (VT), incidence of ventricular fibrillation (VF) and arrhythmia score were assessed. Cardiac levels of creatinine kinase-MB (CK-MB), Malondialdehyde (MDA), superoxide dismutase (SOD), endothelin-1 (ET-1), ATP content, and Na+/K+-ATPase pump activity were measured. TH (0.1 mg/kg) in combination with IRB (5, 10 and 15 mg/kg) produced significant decrease in QTc interval duration, ST height, incidence of VT and VF, duration of VT + VF, and arrhythmia score compared to I/R group. All treated groups showed significant decrease in the cardiac levels of: CK-MB, MDA and ET-1 and significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to I/R. TH/IRB + IR (0.1/10 mg/kg) group produced significant decrease in CK-MB, MDA and ET-1 and a significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to other treated groups. In conclusion, angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) decreased arrhythmia score and decreased cardiac damage. These could be explained in part by its ability to decrease oxidative stress and ET-1, increase ATP, and Na+/K+-ATPase pump activity in this rat model of I/R-induced arrhythmia.
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22
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Malek V, Gaikwad AB. Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy. Cardiovasc Res 2020; 115:373-384. [PMID: 30184174 DOI: 10.1093/cvr/cvy226] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 08/28/2018] [Indexed: 01/02/2023] Open
Abstract
Aims LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.
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Affiliation(s)
- Vajir Malek
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, India
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23
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Seferovic JP, Solomon SD, Seely EW. Potential mechanisms of beneficial effect of sacubitril/valsartan on glycemic control. Ther Adv Endocrinol Metab 2020; 11:2042018820970444. [PMID: 33489085 PMCID: PMC7768573 DOI: 10.1177/2042018820970444] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 10/12/2020] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35-40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor-neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin-angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin-angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.
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Affiliation(s)
| | - Scott D. Solomon
- Cardiovascular Division, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA, USA
| | - Ellen W. Seely
- Endocrinology, Diabetes, and Hypertension
Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA,
USA
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24
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Sankhe R, Kinra M, Mudgal J, Arora D, Nampoothiri M. Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury. Toxicol Mech Methods 2019; 30:88-99. [PMID: 31532266 DOI: 10.1080/15376516.2019.1669246] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.
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Affiliation(s)
- Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Manas Kinra
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.,School of Pharmacy and Pharmacology, MHIQ, QUM Network, Griffith University, Gold Coast, Australia
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
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25
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Arendse LB, Danser AHJ, Poglitsch M, Touyz RM, Burnett JC, Llorens-Cortes C, Ehlers MR, Sturrock ED. Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure. Pharmacol Rev 2019; 71:539-570. [PMID: 31537750 PMCID: PMC6782023 DOI: 10.1124/pr.118.017129] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure-regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.
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Affiliation(s)
- Lauren B Arendse
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - A H Jan Danser
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Marko Poglitsch
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Rhian M Touyz
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - John C Burnett
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Catherine Llorens-Cortes
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Mario R Ehlers
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
| | - Edward D Sturrock
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa (L.B.A., E.D.S.); Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands (A.H.J.D.); Attoquant Diagnostics, Vienna, Austria (M.P.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota (J.C.B.); Institut National de la Santé et de la Recherche Médicale, Paris, France (C.L.-C.); and Clinical Trials Group, Immune Tolerance Network, San Francisco, California (M.R.E.)
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Haynes R, Judge PK, Staplin N, Herrington WG, Storey BC, Bethel A, Bowman L, Brunskill N, Cockwell P, Hill M, Kalra PA, McMurray JJV, Taal M, Wheeler DC, Landray MJ, Baigent C. Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease. Circulation 2019; 138:1505-1514. [PMID: 30002098 DOI: 10.1161/circulationaha.118.034818] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown. METHODS The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual's baseline measured GFR. All analyses were by intention to treat. RESULTS In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4-7.4) and 2.1 (95% CI, 1.0-3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8-23) and 18% (95% CI, 11-25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75-1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96-1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups. CONCLUSIONS Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. CLINICAL TRIAL REGISTRATION URL: http://www.isrctn.com . Unique identifier: ISRCTN11958993.
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Affiliation(s)
- Richard Haynes
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Parminder K Judge
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Natalie Staplin
- Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - William G Herrington
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Benjamin C Storey
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Angelyn Bethel
- Nuffield Department of Population Health, and Diabetes Trials Unit, Radcliffe Department of Medicine (A.B.), University of Oxford, UK
| | - Louise Bowman
- Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Nigel Brunskill
- Department of Infection, Immunity and Inflammation, University of Leicester, UK (N.B.)
| | - Paul Cockwell
- Department of Nephrology, University Hospitals Birmingham, UK (P.C.)
| | - Michael Hill
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Philip A Kalra
- Department of Nephrology, Salford Royal Hospital NHS Foundation Trust, UK (P.A.K.)
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (J.J.V.M.)
| | - Maarten Taal
- Faculty of Medicine and Health Sciences, University of Nottingham, UK (M.T.)
| | - David C Wheeler
- Centre for Nephrology, University College London, UK (D.C.W.)
| | - Martin J Landray
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
| | - Colin Baigent
- Medical Research Council Population Health Research Unit (R.H., P.K.J., W.G.H., B.C.S., M.H., M.J.L., C.B.), University of Oxford, UK.,Clinical Trial Service Unit (R.H., P.K.J., N.S., W.G.H., B.C.S., L.B., M.H., M.J.L., C.B.), University of Oxford, UK
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27
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van de Wouw J, Broekhuizen M, Sorop O, Joles JA, Verhaar MC, Duncker DJ, Danser AHJ, Merkus D. Chronic Kidney Disease as a Risk Factor for Heart Failure With Preserved Ejection Fraction: A Focus on Microcirculatory Factors and Therapeutic Targets. Front Physiol 2019; 10:1108. [PMID: 31551803 PMCID: PMC6737277 DOI: 10.3389/fphys.2019.01108] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 08/12/2019] [Indexed: 12/11/2022] Open
Abstract
Heart failure (HF) and chronic kidney disease (CKD) co-exist, and it is estimated that about 50% of HF patients suffer from CKD. Although studies have been performed on the association between CKD and HF with reduced ejection fraction (HFrEF), less is known about the link between CKD and heart failure with preserved ejection fraction (HFpEF). Approximately, 50% of all patients with HF suffer from HFpEF, and this percentage is projected to rise in the coming years. Therapies for HFrEF are long established and considered quite successful. In contrast, clinical trials for treatment of HFpEF have all shown negative or disputable results. This is likely due to the multifactorial character and the lack of pathophysiological knowledge of HFpEF. The typical co-existence of HFpEF and CKD is partially due to common underlying comorbidities, such as hypertension, dyslipidemia and diabetes. Macrovascular changes accompanying CKD, such as hypertension and arterial stiffening, have been described to contribute to HFpEF development. Furthermore, several renal factors have a direct impact on the heart and/or coronary microvasculature and may underlie the association between CKD and HFpEF. These factors include: (1) activation of the renin-angiotensin-aldosterone system, (2) anemia, (3) hypercalcemia, hyperphosphatemia and increased levels of FGF-23, and (4) uremic toxins. This review critically discusses the above factors, focusing on their potential contribution to coronary dysfunction, left ventricular stiffening, and delayed left ventricular relaxation. We further summarize the directions of novel treatment options for HFpEF based on the contribution of these renal drivers.
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Affiliation(s)
- Jens van de Wouw
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Michelle Broekhuizen
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, Netherlands.,Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands.,Division of Neonatology, Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Oana Sorop
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands
| | - Dirk J Duncker
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - A H Jan Danser
- Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Daphne Merkus
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
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Okamoto R, Ali Y, Hashizume R, Suzuki N, Ito M. BNP as a Major Player in the Heart-Kidney Connection. Int J Mol Sci 2019; 20:ijms20143581. [PMID: 31336656 PMCID: PMC6678680 DOI: 10.3390/ijms20143581] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 02/07/2023] Open
Abstract
Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.
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Affiliation(s)
- Ryuji Okamoto
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
| | - Yusuf Ali
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Ryotaro Hashizume
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Noboru Suzuki
- Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
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29
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Effects of dual angiotensin type 1 receptor/neprilysin inhibition vs. angiotensin type 1 receptor inhibition on target organ injury in the stroke-prone spontaneously hypertensive rat. J Hypertens 2019; 36:1902-1914. [PMID: 29916993 DOI: 10.1097/hjh.0000000000001762] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES The combination of AT1 blocker/neutroendopeptidase neprilysin inhibition (ARNi) represents an interesting approach to reduce cardiovascular risk in hypertension. We assessed the efficacy of ARNi, compared with angiotensin II type 1 receptor blockade alone, on blood pressure (BP) and on protection from target organ damage development in the stroke-prone spontaneously hypertensive rat (SHRSP). METHODS In high-salt fed SHRSP, we assessed plasma and tissue natriuretic peptides, urinary volume, BP and body weight over a short-term treatment (6 weeks) with either ARNi (sacubitril/valsartan 68 mg/kg per day) or valsartan (30 mg/kg per day), protection from stroke and renal damage (as documented by proteinuria) over 4 months of treatment with either sacubitril/valsartan or valsartan; the ability of either treatment to reduce progression of cerebrovascular and renal damage after 2 weeks of high-salt diet. RESULTS Higher levels of plasma and tissue atrial natriuretic peptide, of urinary cyclic guanosine 3'5'monophosphate and urine volumes, along with lower BP levels, were found upon sacubitril/valsartan as compared with valsartan over the short-term treatment. Sacubitril/valsartan caused a significant reduction of both BP and proteinuria levels and complete prevention of stroke over the long-term treatment. Once organ damage was established, a significant delay of its progression was observed with sacubitril/valsartan. CONCLUSION The dual angiotensin II type 1 receptor/neutroendopeptidase inhibition significantly increased atrial natriuretic peptide level and reduced BP. Complete prevention of stroke was achieved in this model. The ability of sacubitril/valsartan to reduce organ damage progression was superior to that of valsartan alone. ARNi may represent a highly effective therapeutic agent to protect from target organ damage development in hypertension.
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30
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Volpe M, Rubattu S, Battistoni A. ARNi: A Novel Approach to Counteract Cardiovascular Diseases. Int J Mol Sci 2019; 20:ijms20092092. [PMID: 31035359 PMCID: PMC6539682 DOI: 10.3390/ijms20092092] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/23/2019] [Accepted: 04/25/2019] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases (CVDs) still represent the greatest burden on healthcare systems worldwide. Despite the enormous efforts over the last twenty years to limit the spread of cardiovascular risk factors, their prevalence is growing and control is still suboptimal. Therefore, the availability of new therapeutic tools that may interfere with different pathophysiological pathways to slow the establishment of clinical CVDs is important. Previously, the inhibition of neurohormonal systems, namely the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system, has proven to be useful in the treatment of many CVDs. Attempts have recently been made to target an additional hormonal system, that of the natriuretic peptides (NPs), which, when dysregulated, can also play a role in the development CVDs. Indeed, a new class of drug, the angiotensin receptor–neprilysin inhibitors (ARNi), has the ability to counteract the effects of angiotensin II as well as to increase the activity of NPs. ARNi have already been proven to be effective in the treatment of heart failure with reduced ejection fraction. New evidence has suggested that, in the next years, the field of ARNi application will widen to include other CVDs, such as heart failure, with preserved ejection fraction and hypertension.
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Affiliation(s)
- Massimo Volpe
- Department of Clinical and Molecular Medicine; School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
- IRCCS Neuromed, 86077 Pozzilli, Italy.
| | - Speranza Rubattu
- Department of Clinical and Molecular Medicine; School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
- IRCCS Neuromed, 86077 Pozzilli, Italy.
| | - Allegra Battistoni
- Department of Clinical and Molecular Medicine; School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
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31
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Boccellino M, Di Domenico M, Donniacuo M, Bitti G, Gritti G, Ambrosio P, Quagliuolo L, Rinaldi B. AT1-receptor blockade: Protective effects of irbesartan in cardiomyocytes under hypoxic stress. PLoS One 2018; 13:e0202297. [PMID: 30356256 PMCID: PMC6200178 DOI: 10.1371/journal.pone.0202297] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/31/2018] [Indexed: 12/21/2022] Open
Abstract
Hypoxia induces myocardial injury through the activation of inflammatory and oxidative processes. The pivotal role of the renin angiotensin system (RAS) in the pathogenesis of cardiovascular diseases has been firmly established in clinical trials and practice; in fact many experimental and clinical data have highlighted that its inhibition has a cardioprotective role. Activated RAS also stimulates inflammation directly inducing proinflammatory and oxidative gene expression. This study aimed to investigate the protective role of a pre-treatment (10 and 100 μM) with irbesartan on injury induced by 24 h of hypoxia in HL-1 cardiomyocytes; in particular, we have analyzed the natriuretic peptide (BNP) expression, a biomarker able to modulate inflammatory reaction to cardiac injury and some markers involved in oxidative stress and inflammation. Our results demonstrated that a pre-treatment with 100 μM irbesartan significantly increased SOD activity and catalase expression of 15 and 25%, respectively, compared to hypoxic cells (P<0.05). On the other hand, it was able to reduce the release of peroxynitrite and iNOS protein expression of 20 and 50% respectively (P<0.05). In addition irbesartan exerts an anti-inflammatory activity reducing Toll-like receptors (TLRs)-2 and -4 mRNA expression, TNF-alpha expression and activity (20%) and increasing the expression of the cytokine IL-17 (40%) (P<0.05 vs hypoxia). Our findings also showed that BNP induced by ischemia was significantly and in a concentration-dependent manner reduced by irbesartan. The findings of our study demonstrated that the AT1 receptor antagonist irbesartan exerts a protective role in an in vitro hypoxic condition reducing oxidative stress and inflammation.
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Affiliation(s)
- Mariarosaria Boccellino
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Marina Di Domenico
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United States of America
- * E-mail:
| | - Maria Donniacuo
- Department of Experimental Medicine, Section of Pharmacology, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giuseppe Bitti
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Giulia Gritti
- Department of Experimental Medicine, Section of Pharmacology, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Pasqualina Ambrosio
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Lucio Quagliuolo
- Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
| | - Barbara Rinaldi
- Department of Experimental Medicine, Section of Pharmacology, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
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Packer M. Role of the sodium-hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes. Diabetes Obes Metab 2018; 20:800-811. [PMID: 29227582 DOI: 10.1111/dom.13191] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 01/19/2023]
Abstract
Diabetes is characterized by increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
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Abstract
Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer’s disease.
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Roksnoer LCW, Uijl E, de Vries R, Garrelds IM, Jan Danser AH. Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney. Eur J Pharmacol 2018; 824:128-132. [PMID: 29432709 DOI: 10.1016/j.ejphar.2018.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 10/18/2022]
Abstract
Increasing the degree of renin-angiotensin system (RAS) blockade by combining ≥2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3'5' monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only.
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Affiliation(s)
- Lodi C W Roksnoer
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, room EE1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Estrellita Uijl
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, room EE1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - René de Vries
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, room EE1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Ingrid M Garrelds
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, room EE1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - A H Jan Danser
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, room EE1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
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Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data. Nephrol Dial Transplant 2017; 32:2043-2051. [PMID: 27646835 PMCID: PMC5837485 DOI: 10.1093/ndt/gfw321] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 07/24/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. METHODS UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. RESULTS Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. CONCLUSIONS UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.
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Prasad T, Roksnoer LCW, Zhu P, Verma A, Li Y, Batenburg WW, de Vries R, Danser AHJ, Li Q. Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye. Invest Ophthalmol Vis Sci 2017; 57:6722-6730. [PMID: 27951594 PMCID: PMC5156511 DOI: 10.1167/iovs.16-20289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose Dysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocin-induced diabetic transgenic (mRen2)27 rats. Methods Adult male diabetic (mRen2)27 rats were followed for 5 or 12 weeks. Treatment with vehicle, irbesartan (ARB), or ARB combined with the neprilysin inhibitor thiorphan (irbesartan+thiorphan [ARNI]) occurred during the final 3 weeks. Retinal cell death, gliosis, and capillary loss were evaluated. Real-time polymerase chain reaction (RT-PCR) analyses were performed to quantify the retinal level of inflammatory cell markers. Results Both ARB- and ARNI-treated groups showed similarly reduced retinal apoptotic cell death, gliosis, and capillary loss compared to the vehicle-treated group in the 5-week study. Treatment with ARNI reduced the expression of inflammatory markers more than ARB treatment in the 5-week study. In the 12-week study, ARNI treatment showed significantly more reduction in apoptotic cell death (51% vs. 25% reduction), and capillary loss (68% vs. 43% reduction) than ARB treatment. Conclusions Treatment with ARNI provides better protection against DR in diabetic (mRen2)27 transgenic rats, compared to ARB alone. This approach may be a promising treatment option for patients with DR.
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Affiliation(s)
- Tuhina Prasad
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States
| | - Lodi C W Roksnoer
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Ping Zhu
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States
| | - Amrisha Verma
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States
| | - Yiming Li
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States
| | - Wendy W Batenburg
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - René de Vries
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Qiuhong Li
- Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States
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Malek V, Gaikwad AB. Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications? Biomed Pharmacother 2017; 90:752-759. [DOI: 10.1016/j.biopha.2017.04.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 03/31/2017] [Accepted: 04/10/2017] [Indexed: 11/26/2022] Open
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Abstract
Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy.
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Affiliation(s)
- Duncan J Campbell
- St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.,University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia
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