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Cheungpasitporn W, Krisanapan P, Suppadungsuk S, Thongprayoon C, Fülöp T, Miao J, Soliman KM, Ho YS. Research trends and performance of endothelin A receptor antagonist in kidney care: a bibliometric analysis. Ren Fail 2025; 47:2487212. [PMID: 40211733 PMCID: PMC11995767 DOI: 10.1080/0886022x.2025.2487212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 03/11/2025] [Accepted: 03/22/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Endothelin A receptor antagonists (ERAs) have emerged as pivotal therapeutic agents in managing pulmonary hypertension (PH) and various kidney disorders, including chronic kidney disease (CKD) and proteinuric glomerular diseases such as IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). Although initially developed for pulmonary applications, recent research has highlighted their renoprotective effects, expanding their role in nephrology. This study presents a comprehensive bibliometric analysis of global research trends, key contributors, and emerging applications of ERAs in kidney care over the past three decades. METHODS A bibliometric analysis was performed using the Science Citation Index Expanded database (1992-2023). Relevant kidney-related publications were identified through specific keyword searches. Author performance was assessed using the Y-index. RESULTS ERA-related research has shown significant growth, particularly in nephrology. The United States and the University of Groningen lead in publication volume and international collaborations, with H.J.L. Heerspink emerging as a key contributor. While PH remains the dominant research focus, nephrology applications are rapidly increasing, particularly in CKD, diabetic nephropathy (DN), and glomerular diseases. A major milestone was the accelerated FDA approval of sparsentan for IgAN in 2023, followed by full approval in 2024 based on confirmatory efficacy data. However, challenges such as fluid retention and cardiovascular risks remain, necessitating further investigation into optimized ERA therapies, including combination strategies with SGLT2 inhibitors. CONCLUSIONS The expanding role of ERAs in nephrology underscores their potential in treating proteinuric kidney diseases. Ongoing international collaborations are advancing research on ERA safety, efficacy, and novel therapeutic strategies, supporting their broader clinical application.
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Affiliation(s)
| | - Pajaree Krisanapan
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
- Department of Nephrology, Department of Internal Medicine, Thammasat University, Khlong Nueng, Thailand
| | - Supawadee Suppadungsuk
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
- Faculty of Medicine Ramathibodi Hospital, Chakri Naruebodindra Medical Institute, Bang Pla, Thailand
| | - Charat Thongprayoon
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
| | - Tibor Fülöp
- Medical Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Jing Miao
- Department of Medicine, Division of Nephrology, Mayo Clinic, Rochester, MN, USA
| | - Karim M. Soliman
- Medical Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, USA
| | - Yuh-Shan Ho
- Trend Research Centre, Asia University, Taichung, Taiwan
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Ma X, Liang Y, Chen W, Zheng L, Lin H, Zhou T. The role of endothelin receptor antagonists in kidney disease. Ren Fail 2025; 47:2465810. [PMID: 40015728 PMCID: PMC11869344 DOI: 10.1080/0886022x.2025.2465810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 03/01/2025] Open
Abstract
Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.
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Affiliation(s)
- Xiaoting Ma
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Yuyang Liang
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Wenmin Chen
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Lingqian Zheng
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Haishan Lin
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, China
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Makled MN, Makled NN, Abdel-Rahman AM, Sharawy MH. Inhibition of p75 NTR/p53 axis by ambrisentan suppresses apoptosis and oxidative stress-mediated renal damage in a cisplatin AKI model. Chem Biol Interact 2025; 408:111408. [PMID: 39892498 DOI: 10.1016/j.cbi.2025.111408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/03/2025]
Abstract
Cisplatin (CP) is a potent antineoplastic agent that triggers nephrotoxicity as a major adverse effect which can cause treatment interruptions and limitations to its clinical use. Nephrotoxicity associated with CP involves inflammation, oxidative stress, and apoptosis in kidney tubules. The objective of this work was to assess the effect of the blockade of endothelin-1 (ET-1) receptor with ambrisentan on altered renal function induced by CP. Swiss albino mice were assigned into control, CP, CP/Amb-5, and CP/Amb-10 groups. Ambrisentan improved kidney function (serum creatinine and BUN) and histopathological changes in comparison to CP-treated group. Ambrisentan significantly reduced protein expression of p75NTR and protein level of JNK influencing renal apoptosis as evidenced by reducing p53, caspase-3, and Bax levels and elevating Bcl-2 level (p < 0.05 vs CP group). Moreover, vasodilatory effect of ambrisentan was indicated by significant increase in level of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) (p < 0.05 vs CP group). Ambrisentan also significantly restored oxidative balance in renal tissues as evidenced by reduced malondialdehyde and increased total antioxidant capacity and superoxide dismutase activity, in addition to decreasing nitric oxide levels (p < 0.05 vs CP group). This protective effect of ambrisentan might be mediated through the downregulation of death receptor, P75NTR that in turn restores renal blood flow and oxidative balance and regulates p53, VEGF/eNOS, NF-κB, and Bcl-2/Bax/caspase-3 signaling.
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Affiliation(s)
- Mirhan N Makled
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Noran N Makled
- Department of Urology, Faculty of Medicine, Damietta University, Damietta, Egypt; Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Ahmed M Abdel-Rahman
- Department of Nephrology, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Maha H Sharawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Mathur M, Sahay M, Pereira BJG, Rizk DV. State-of-Art Therapeutics in IgA Nephropathy. Indian J Nephrol 2024; 34:417-430. [PMID: 39372635 PMCID: PMC11450772 DOI: 10.25259/ijn_319_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 10/08/2024] Open
Abstract
Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.
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Affiliation(s)
| | - Manisha Sahay
- Department of Nephrology, Osmania General Hospital and Osmania Medical College, Hyderabad, India
| | | | - Dana V. Rizk
- Department of Medicine, Division of Nephrology, University of Alabama, Birmingham, USA
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Liu Q, Chen J, Zeng A, Song L. Pharmacological functions of salidroside in renal diseases: facts and perspectives. Front Pharmacol 2024; 14:1309598. [PMID: 38259279 PMCID: PMC10800390 DOI: 10.3389/fphar.2023.1309598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
Rhodiola rosea is a valuable functional medicinal plant widely utilized in China and other Asian countries for its anti-fatigue, anti-aging, and altitude sickness prevention properties. Salidroside, a most active constituent derived from Rhodiola rosea, exhibits potent antioxidative, hypoxia-resistant, anti-inflammatory, anticancer, and anti-aging effects that have garnered significant attention. The appreciation of the pharmacological role of salidroside has burgeoned over the last decade, making it a beneficial option for the prevention and treatment of multiple diseases, including atherosclerosis, Alzheimer's disease, Parkinson's disease, cardiovascular disease, and more. With its anti-aging and renoprotective effects, in parallel with the inhibition of oxidative stress and inflammation, salidroside holds promise as a potential therapeutic agent for kidney damage. This article provides an overview of the microinflammatory state in kidney disease and discuss the current therapeutic strategies, with a particular focus on highlighting the recent advancements in utilizing salidroside for renal disease. The potential mechanisms of action of salidroside are primarily associated with the regulation of gene and protein expression in glomerular endothelial cells, podocytes, renal tubule cells, renal mesangial cells and renal cell carcinoma cell, including TNF-α, TGF-β, IL-1β, IL-17A, IL-6, MCP-1, Bcl-2, VEGF, ECM protein, caspase-3, HIF-1α, BIM, as well as the modulation of AMPK/SIRT1, Nrf2/HO-1, Sirt1/PGC-1α, ROS/Src/Cav-1, Akt/GSK-3β, TXNIP-NLRP3, ERK1/2, TGF-β1/Smad2/3, PI3K/Akt, Wnt1/Wnt3a β-catenin, TLR4/NF-κB, MAPK, JAK2/STAT3, SIRT1/Nrf2 pathways. To the best of our knowledge, this review is the first to comprehensively cover the protective effects of salidroside on diverse renal diseases, and suggests that salidroside has great potential to be developed as a drug for the prevention and treatment of metabolic syndrome, cardiovascular and cerebrovascular diseases and renal complications.
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Affiliation(s)
- Qiong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jianzhu Chen
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Sinha SK, Nicholas SB. Pathomechanisms of Diabetic Kidney Disease. J Clin Med 2023; 12:7349. [PMID: 38068400 PMCID: PMC10707303 DOI: 10.3390/jcm12237349] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 03/15/2024] Open
Abstract
The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- College of Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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Heerspink HJL, Kiyosue A, Wheeler DC, Lin M, Wijkmark E, Carlson G, Mercier AK, Åstrand M, Ueckert S, Greasley PJ, Ambery P. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet 2023; 402:2004-2017. [PMID: 37931629 DOI: 10.1016/s0140-6736(23)02230-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin. METHODS ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m2 or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed. FINDINGS Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m2 [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0-1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and -27·0% (90% CI -38·4 to -13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group. INTERPRETATION Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy. FUNDING AstraZeneca.
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Affiliation(s)
- Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; The George Institute for Global Health, Sydney, NSW, Australia.
| | | | - David C Wheeler
- Department of Nephrology, University College London, London, UK
| | - Min Lin
- Biometrics Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Emma Wijkmark
- Biometrics Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Glenn Carlson
- Clinical Development, Late Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
| | - Anne-Kristina Mercier
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Magnus Åstrand
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Sebastian Ueckert
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter J Greasley
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Phil Ambery
- Clinical Late Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Smeijer JD, Kohan DE, Rossing P, Correa-Rotter R, Liew A, Tang SCW, de Zeeuw D, Gansevoort RT, Ju W, Lambers Heerspink HJ. Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease. Cardiovasc Diabetol 2023; 22:251. [PMID: 37716952 PMCID: PMC10505320 DOI: 10.1186/s12933-023-01964-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/14/2023] [Indexed: 09/18/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. METHODS We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. RESULTS In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). CONCLUSIONS More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. TRIAL REGISTRATION RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.
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Affiliation(s)
- J David Smeijer
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ricardo Correa-Rotter
- National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico
| | - Adrian Liew
- Mount Elizabeth Novena Hospital, Singapore, Singapore
- George Institute for Global Health, Newtown, Australia
| | - Sydney C W Tang
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ron T Gansevoort
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wenjun Ju
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hiddo J Lambers Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
- George Institute for Global Health, Newtown, Australia.
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Zhang S, Li X, Liu S, Zhang W, Li M, Qiao C. Research progress on the role of ET-1 in diabetic kidney disease. J Cell Physiol 2023; 238:1183-1192. [PMID: 37063089 DOI: 10.1002/jcp.31023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/16/2023] [Accepted: 04/03/2023] [Indexed: 04/18/2023]
Abstract
Diabetic kidney disease (DKD) is one of the common complications of diabetes mellitus, which usually progresses to end-stage renal disease and causes great damage to the health of patients. Endothelin-1 (ET-1), a molecule closely associated with the progression of DKD, has increased expression in response to high glucose stimulation and is involved in hemodynamic changes, inflammation, glomerular and tubular dysfunction in the kidney, causing an increase in proteinuria and a decrease in glomerular filtration function, ultimately leading to glomerulosclerosis and renal failure. This paper aims to review the molecular level changes, regulatory mechanisms, and mechanisms of action of ET-1 under DKD, clinical trials of ET-1 receptor antagonists in recent years and current problems, to provide basic information and new research directions and ideas for the treatment of DKD and ET-1-related research.
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Affiliation(s)
- Shenghao Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiaodan Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Siyu Liu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Wanting Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Meinuo Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chen Qiao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
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Morales E, Sandino J, Galindo M. Lupus nephropathy beyond immunosuppression: Searching for nephro and cardioprotection. FRONTIERS IN NEPHROLOGY 2023; 3:1105676. [PMID: 37675340 PMCID: PMC10479677 DOI: 10.3389/fneph.2023.1105676] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/10/2023] [Indexed: 09/08/2023]
Abstract
Renal involvement in systemic lupus erythematosus (SLE) represents one of the most frequent organ manifestations, often leading to end-stage kidney disease (ESKD). Several therapies have been tested in patients with lupus nephritis (LN) to prevent further organ damage. The effectiveness of immunosuppressive therapy as a treatment for LN is abundant, supported by multiple clinical trials that have shown its efficacy in preventing the development of chronic kidney disease (CKD). In addition to immunosuppressive therapy, several traditional and recent therapies aimed at nephroprotection in patients with proteinuric chronic kidney disease are gaining importance in the setting of LN. Thus, immunosuppressive therapy should be accompanied by nephro- and cardioprotective measures to control cardiovascular risk factors and proteinuria to ensure a better renal prognosis. Despite this, the literature on these specific measures is relatively scarce, with recommendations focused on the blockade of the renin-angiotensin-aldosterone system (RAAS). This review explores the pharmacological options available for cardiovascular and renal protection outside the usual treatment schemes.
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Affiliation(s)
- Enrique Morales
- Department of Nephrology, University Hospital “12 de Octubre”, Madrid, Spain
- Research Institute of University Hospital “12 de Octubre” (imas12), Madrid, Spain
- Department of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Justo Sandino
- Department of Nephrology, University Hospital “12 de Octubre”, Madrid, Spain
- Research Institute of University Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - María Galindo
- Research Institute of University Hospital “12 de Octubre” (imas12), Madrid, Spain
- Department of Medicine, Complutense University of Madrid, Madrid, Spain
- Department of Rheumatology, University Hospital “12 de Octubre”, Madrid, Spain
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11
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12
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Rivera-Gonzalez O, Case CT, Wilson NA, Speed JS, Taylor EB. Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus. Am J Physiol Endocrinol Metab 2023; 324:E73-E84. [PMID: 36476039 PMCID: PMC9870584 DOI: 10.1152/ajpendo.00274.2022] [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: 10/17/2022] [Revised: 11/30/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with an increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day) for 4 wk. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T-cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, homeostatic model assessment for insulin resistance, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.NEW & NOTEWORTHY SLE is an autoimmune disease that is associated with obesity, insulin resistance, and elevated endothelin-1. The present study demonstrated that pharmacological inhibition of endothelin receptors decreased body weight, insulin resistance, and adipose tissue inflammation in a murine model of SLE. The therapeutic potential of endothelin receptor antagonists to treat obesity-related diseases and pathophysiological conditions, such as autoimmune diseases and insulin resistance, has become increasingly clear.
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Affiliation(s)
- Osvaldo Rivera-Gonzalez
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Clinton T Case
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Natalie A Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Joshua S Speed
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Erin B Taylor
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
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13
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Yang Y, Xu G. Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:872918. [PMID: 35663316 PMCID: PMC9161673 DOI: 10.3389/fendo.2022.872918] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium-glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin-angiotensin-aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
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14
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Angeli F, Verdecchia P, Reboldi G. Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension. Cardiol Ther 2021; 10:397-406. [PMID: 34251649 PMCID: PMC8555037 DOI: 10.1007/s40119-021-00233-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Indexed: 12/19/2022] Open
Abstract
Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.
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Affiliation(s)
- Fabio Angeli
- Department of Medicine and Surgery, University of Insubria, Varese, Italy. .,Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institutes, IRCCS Tradate, Varese, Italy.
| | - Paolo Verdecchia
- Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy
| | - Gianpaolo Reboldi
- Department of Medicine and Centro di Ricerca Clinica e Traslazionale (CERICLET), University of Perugia, Perugia, Italy
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15
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Franzén S, Näslund E, Wang H, Frithiof R. Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs. Am J Physiol Regul Integr Comp Physiol 2021; 321:R12-R20. [PMID: 34009032 DOI: 10.1152/ajpregu.00073.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg-1·h-1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of <50 mmHg for 30 min. Plasma ANG II levels, hemodynamics and oxygenation were assessed 60 min prehemorrhage, 30-min after the start of hemorrhage, and 60 min posthemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma ANG II levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, ANG II antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.
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Affiliation(s)
- Stephanie Franzén
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
| | - Erik Näslund
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.,Centre for Research and Development, Uppsala University/Region Gävleborg, Gavle, Sweden
| | - Helen Wang
- Department of Medical Biochemistry and Microbiology, Infections and Defenses, Uppsala University, Uppsala, Sweden
| | - Robert Frithiof
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
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16
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An Update on the Current State of Management and Clinical Trials for IgA Nephropathy. J Clin Med 2021; 10:jcm10112493. [PMID: 34200024 PMCID: PMC8200196 DOI: 10.3390/jcm10112493] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 12/31/2022] Open
Abstract
IgA nephropathy remains the most common primary glomerular disease worldwide. It affects children and adults of all ages, and is a leading cause of end-stage kidney disease, making it a considerable public health issue in many countries. Despite being initially described over 50 years ago, there are still no disease specific treatments, with current management for most patients being focused on lifestyle measures and renin-angiotensin-aldosterone system blockade. However, significant advances in the understanding of its pathogenesis have been made particularly over the past decade, leading to great interest in developing new therapeutic strategies, and a significant rise in the number of interventional clinical trials being performed. In this review, we will summarise the current state of management of IgAN, and then describe major areas of interest where new therapies are at their most advanced stages of development, that include the gut mucosal immune system, B cell signalling, the complement system and non-immune modulators. Finally, we describe clinical trials that are taking place in each area and explore future directions for translational research.
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17
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Wang XH, Ao QG, Cheng QL. Caloric restriction inhibits renal artery ageing by reducing endothelin-1 expression. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:979. [PMID: 34277779 PMCID: PMC8267285 DOI: 10.21037/atm-21-2218] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/28/2021] [Indexed: 12/31/2022]
Abstract
Background The renal artery plays a central role in renal perfusion and is critical for proper renal function. Ageing is an independent risk factor for both impaired renal function and vascular disorders, and associated with an increase in the expression of the vasoconstrictor endothelin-1 (ET-1), and caloric restriction (CR) without malnutrition has been shown to be an effective inhibitor of renal dysfunction induced by ageing. The objective of this study was to determine whether CR-mediated alleviation of renal dysfunction is mediated by ET-1 expression. Methods The young (2 months, 2 M) and old (12 months, 12 M) Sprague-Dawley male rats were used and fed ad libitum. The 12-month-old rats were further divided into 12 M and 12 M-caloric restriction (CR) (30% calorie restriction). After 8 weeks, the renal tissues were showed by PAS staining, and age-related metabolic parameters and renal functions were detected in each group of rats. The inflammatory cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) were analyzed using ELISA. The mRNA and protein expression in the renal artery were analysis by qRT-PCR and Immunoblot analysis. Results Ageing was associated with significant increases in 24 h urine protein content and serum triglyceride and cholesterol in 12 M rats, both of which were significantly inhibited in 12 M-CR. The mRNA expression and the secretion of IL-6, IL-1β, TNF-α, and TGF-β1 in the renal artery was significantly increased with ageing and inhibited by CR. CR also inhibited ageing-induced Edn1 (encoding ET-1) mRNA and protein expression in the renal artery. In addition, CR could regulate ET-1 expression by inhibiting the activation of NF-κB signaling and activation and induction in the expression of NF-E2-related factor 2 (Nrf2) and histone deacetylase and gene repressor sirtuin 1 (SIRT1), both of which play a central role in mitigating oxidative stress in young rats. Conclusions Moderate CR can reverse the ageing related kidney dysfunction by reducing the ET-1 expression. CR might be used as an alternative to prevent the ageing induced renal artery dysfunction.
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Affiliation(s)
- Xiao-Hua Wang
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qiang-Guo Ao
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qing-Li Cheng
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
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18
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Woodhams L, Sim TF, Chalmers L, Yeap B, Green D, Schlaich M, Schultz C, Hillis G. Diabetic kidney disease in type 2 diabetes: a review of pathogenic mechanisms, patient-related factors and therapeutic options. PeerJ 2021; 9:e11070. [PMID: 33976959 PMCID: PMC8061574 DOI: 10.7717/peerj.11070] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/16/2021] [Indexed: 12/23/2022] Open
Abstract
The global prevalence of diabetic kidney disease is rapidly accelerating due to an increasing number of people living with type 2 diabetes. It has become a significant global problem, increasing human and financial pressures on already overburdened healthcare systems. Interest in diabetic kidney disease has increased over the last decade and progress has been made in determining the pathogenic mechanisms and patient-related factors involved in the development and pathogenesis of this disease. A greater understanding of these factors will catalyse the development of novel treatments and influence current practice. This review summarises the latest evidence for the factors involved in the development and progression of diabetic kidney disease, which will inform better management strategies targeting such factors to improve therapeutic outcomes in patients living with diabetes.
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Affiliation(s)
- Louise Woodhams
- Curtin Medical School, Curtin University of Technology, Perth, Western Australia, Australia
| | - Tin Fei Sim
- Curtin Medical School, Curtin University of Technology, Perth, Western Australia, Australia
| | - Leanne Chalmers
- Curtin Medical School, Curtin University of Technology, Perth, Western Australia, Australia
| | - Bu Yeap
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia.,Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Daniel Green
- School of Human Sciences (Exercise and Sport Sciences), The University of Western Australia, Perth, Western Australia, Australia
| | - Markus Schlaich
- Medical School, The University of Western Australia, Perth, Western Australia, Australia.,Department of Cardiology and Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia.,Neurovascular Hypertension and Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, Western Australia, Australia
| | - Carl Schultz
- Medical School, The University of Western Australia, Perth, Western Australia, Australia.,Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - Graham Hillis
- Medical School, The University of Western Australia, Perth, Western Australia, Australia.,Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia
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19
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Empagliflozin Inhibits IL-1β-Mediated Inflammatory Response in Human Proximal Tubular Cells. Int J Mol Sci 2021; 22:ijms22105089. [PMID: 34064989 PMCID: PMC8151056 DOI: 10.3390/ijms22105089] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/04/2021] [Accepted: 05/10/2021] [Indexed: 12/20/2022] Open
Abstract
SGLT2 inhibitor-related nephroprotection is—at least partially—mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i.
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20
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Chen L, Wu J, Hu B, Liu C, Wang H. The Role of Cell Division Autoantigen 1 (CDA1) in Renal Fibrosis of Diabetic Nephropathy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6651075. [PMID: 33997036 PMCID: PMC8102118 DOI: 10.1155/2021/6651075] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 04/05/2021] [Accepted: 04/16/2021] [Indexed: 01/10/2023]
Abstract
The common kidney disease diabetic nephropathy (DN) accounts for significant morbidity and mortality in patients with diabetes, and its effective diagnosis in incipient stages is still lacking. Renal fibrosis is the main pathological feature of DN. Cell division autoantigen 1 (CDA1), a phosphorylated protein encoded by TSPYL2 on the X chromosome, plays a fibrogenic role by modulating the transforming growth factor-β (TGF-β) signaling, but the exact mechanism remains unclear. TGF-β signaling has been recognized as the key factor in promoting the development and progression of DN. At present, strict control of blood sugar and blood pressure can significantly lower the development and progression of DN in the early stages, and many studies have shown that blocking TGF-β signaling can delay the progress of DN. However, TGF-β is a multifunctional cytokine. Its direct intervention may result in increased side effects. Therefore, the targeted intervention of CDA1 not only can block the TGF-β signaling pathway but also can reduce these side effects. In this article, we review the main physiological roles of CDA1, with particular attention to its effect and potential mechanism in the renal fibrosis of DN.
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Affiliation(s)
- LinLin Chen
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
| | - Jiao Wu
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
| | - Bin Hu
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
| | - Changbai Liu
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
| | - Hu Wang
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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21
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Zhang Q, Yang M, Xiao Y, Han Y, Yang S, Sun L. Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy. Curr Med Chem 2021; 28:1003-1024. [PMID: 31701843 DOI: 10.2174/0929867326666191108160643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.
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Affiliation(s)
- Qin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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22
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Zhou Y, Chi J, Huang Y, Dong B, Lv W, Wang YG. Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta-analysis of randomized controlled trials. Diabet Med 2021; 38:e14411. [PMID: 33000477 DOI: 10.1111/dme.14411] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/10/2020] [Accepted: 09/22/2020] [Indexed: 01/01/2023]
Abstract
AIM To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease. METHODS Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random-effect model to calculate the mean difference or risk ratio with the 95% CI. RESULTS Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference -0.48, 95% CI -0.64 to -0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference -0.58, 95% CI -1.00 to -0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference -0.47, 95% CI -0.57 to -0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose-response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events. CONCLUSIONS Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).
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Affiliation(s)
- Y Zhou
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - J Chi
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y Huang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - B Dong
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - W Lv
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
| | - Y G Wang
- Department of Endocrinology, Affiliated Hospital of Medical College Qingdao University, Qingdao, China
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23
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Abu-Saleh N, Yaseen H, Kinaneh S, Khamaisi M, Abassi Z. Combination of hyperglycaemia and hyperlipidaemia induces endothelial dysfunction: Role of the endothelin and nitric oxide systems. J Cell Mol Med 2020; 25:1884-1895. [PMID: 33369150 PMCID: PMC7882960 DOI: 10.1111/jcmm.15787] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 12/26/2022] Open
Abstract
Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi‐disciplinary approaches including cultured HUVECs and HMEC‐1 as well as knockout mice CByJ.129S7(B6)‐Ldlrtm1Her/J (LDLR−/−) to investigate the mechanisms underlying combined HG and hyperlipidaemia‐induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC‐1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)‐1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET‐1 systems were examined in knockout mice LDLR−/− and their wild‐type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET‐1 production, more than HG or OxLDL when added alone. Overproduction of ET‐1 stems from up‐regulation of endothelin converting enzyme (ECE)‐1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR−/− mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET‐1 and NO2/NO3 levels, when compared with normoglycemic LDLR−/− and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED.
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Affiliation(s)
- Niroz Abu-Saleh
- Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Hiba Yaseen
- Department of Medicine D, Rambam Health Care Campus and Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Safa Kinaneh
- Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Mogher Khamaisi
- Department of Medicine D, Rambam Health Care Campus and Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.,Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel
| | - Zaid Abassi
- Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.,Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
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24
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Zhang L, Xue S, Hou J, Chen G, Xu ZG. Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review. World J Diabetes 2020; 11:553-566. [PMID: 33269066 PMCID: PMC7672789 DOI: 10.4239/wjd.v11.i11.553] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/22/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented. AIM To assess the effectiveness and safety of ER antagonists among patients with DN. METHODS The EMBASE, PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched without any language restrictions. Relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software. Publication bias was assessed using Egger's test with Stata/SE software. RESULTS We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic and diastolic blood pressure were observed in the invention group. CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor /angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Xue
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guang Chen
- Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhong-Gao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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25
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Pirklbauer M, Bernd M, Fuchs L, Staudinger P, Corazza U, Leierer J, Mayer G, Schramek H. Empagliflozin Inhibits Basal and IL-1β-Mediated MCP-1/CCL2 and Endothelin-1 Expression in Human Proximal Tubular Cells. Int J Mol Sci 2020; 21:ijms21218189. [PMID: 33139635 PMCID: PMC7663377 DOI: 10.3390/ijms21218189] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/21/2022] Open
Abstract
SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15- and 19-fold) and ET-1 (3- and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6- and 0.5-fold) and ET-1 (0.3- and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.
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26
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The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ET A Receptor in Mouse Mesenteric Arteries. Adv Pharmacol Pharm Sci 2020; 2020:5070436. [PMID: 32309807 PMCID: PMC7152935 DOI: 10.1155/2020/5070436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 02/20/2020] [Indexed: 11/17/2022] Open
Abstract
Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. The current study explored the effect of mmLDL on the endothelin type A (ETA) receptor in mouse mesenteric arteries in vivo, as well as the role of autophagy in this process. mmLDL was injected via the caudal vein, and the Class III PI3K autophagic pathway inhibitor 3-methyladenine (3-MA) was injected intraperitoneally. The animals were divided into physiological saline (NS), mmLDL, and mmLDL + 3-MA groups. The dose-effect curve of endothelin-1- (ET-1-) induced mesenteric artery contraction was measured using myography, while ETA receptor mRNA expression was detected using real-time polymerase chain reactions, and the protein levels of the ETA receptor, class III PI3K, Beclin-1, LC3 II/I, p62, NF-κB, and p-NF-κB were observed using Western blot analysis. mmLDL significantly strengthened ET-1-induced contraction (the Emax value increased from 184.87 ± 7.46% in the NS group to 319.91 ± 20.31% in the mmLDL group (P < 0.001), and the pEC50 value increased from 8.05 ± 0.05 to 9.11 ± 0.09 (P < 0.01). In addition to upregulating the protein levels of Class III PI3K, Beclin-1, and LC3 II/I and downregulating that of p62, mmLDL significantly increased the mRNA expression and protein level of the ETA receptor and increased the protein level of p-NF-κB. However, these effects were significantly inhibited by 3-MA. mmLDL activates autophagy via the Class III PI3K/Beclin-1 pathway and upregulates the ETA receptor via the downstream NF-κB pathway. Understanding the effect of mmLDL on the ETA receptor and the underlying mechanisms may provide a new idea for the prevention and treatment of cardiovascular diseases.
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27
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Barrera-Chimal J, Jaisser F. Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets. Diabetes Obes Metab 2020; 22 Suppl 1:16-31. [PMID: 32267077 DOI: 10.1111/dom.13969] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/07/2020] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.
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Affiliation(s)
- Jonatan Barrera-Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Investigación en Medicina Traslacional, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Frédéric Jaisser
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
- INSERM U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France
- INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Nancy, France
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28
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Douma LG, Solocinski K, Masten SH, Barral DH, Barilovits SJ, Jeffers LA, Alder KD, Patel R, Wingo CS, Brown KD, Cain BD, Gumz ML. EDN1-AS, A Novel Long Non-coding RNA Regulating Endothelin-1 in Human Proximal Tubule Cells. Front Physiol 2020; 11:209. [PMID: 32231591 PMCID: PMC7082230 DOI: 10.3389/fphys.2020.00209] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/24/2020] [Indexed: 12/23/2022] Open
Abstract
Endothelin-1 (ET-1) is a peptide hormone that functions as a vasoconstrictor in the vasculature, whereas in the collecting duct of the kidney it exerts blood pressure-lowering effects via natriuretic actions. Aberrant ET-1 signaling is associated with several pathological states including hypertension and chronic kidney disease. ET-1 expression is regulated largely through transcriptional control of the gene that encodes ET-1, EDN1. Here we report a long, non-coding RNA (lncRNA) that appears to be antisense to the EDN1 gene, called EDN1-AS. Because EDN1-AS represents a potential novel mechanism to regulate ET-1 expression, we examined the regulation of EDN1-AS expression and action. A putative glucocorticoid receptor response (GR) element upstream of the predicted EDN1-AS transcription start site was identified using the ENCODE database and the UCSC genome browser. Two homozygous deletion clones of the element were generated using CRISPR/Cas9. This deletion resulted in a significant increase in the expression of EDN1-AS, which was associated with increased secretion of ET-1 peptide from HK-2 cells (two-fold increase in KO cells vs. CNTL, n = 7, P < 0.05). Phenotypic characterization of these CRISPR clones revealed a difference in cell growth rates. Using a standard growth assay, we determined that the KO1 clone exhibited a three-fold increase in growth over 8 days compared to control cells (n = 4, P < 0.01) and the KO2 clone exhibited a two-fold increase (n = 4, P < 0.01). These results support a role for EDN1-AS as a novel regulatory mechanism of ET-1 expression and cellular proliferation.
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Affiliation(s)
- Lauren G. Douma
- Department of Medicine, University of Florida, Gainesville, FL, United States
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States
| | - Kristen Solocinski
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Sarah H. Masten
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Dominique H. Barral
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Sarah J. Barilovits
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Lauren A. Jeffers
- Department of Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA, United States
| | - Kareme D. Alder
- Yale University School of Medicine, New Haven, CT, United States
| | - Ravi Patel
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Charles S. Wingo
- Department of Medicine, University of Florida, Gainesville, FL, United States
| | - Kevin D. Brown
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States
| | - Brian D. Cain
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States
| | - Michelle L. Gumz
- Department of Medicine, University of Florida, Gainesville, FL, United States
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States
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Zhang L, Chen L, Gao C, Chen E, Lightle AR, Foulke L, Zhao B, Higgins PJ, Zhang W. Loss of Histone H3 K79 Methyltransferase Dot1l Facilitates Kidney Fibrosis by Upregulating Endothelin 1 through Histone Deacetylase 2. J Am Soc Nephrol 2019; 31:337-349. [PMID: 31843983 DOI: 10.1681/asn.2019070739] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The progression rate of CKD varies substantially among patients. The genetic and epigenetic contributions that modify how individual patients respond to kidney injury are largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l has an antifibrotic effect by repressing Edn1, which encodes endothelin 1 in the connecting tubule/collecting duct. METHODS To determine if deletion of the Dot1l gene is a genetic and epigenetic risk factor through regulating Edn1, we studied four groups of mice: wild-type mice, connecting tubule/collecting duct-specific Dot1l conditional knockout mice (Dot1lAC ), Dot1l and Edn1 double-knockout mice (DEAC ), and Edn1 connecting tubule/collecting duct-specific conditional knockout mice (Edn1AC ), under three experimental conditions (streptozotocin-induced diabetes, during normal aging, and after unilateral ureteral obstruction). We used several approaches (colocalization, glutathione S-transferase pulldown, coimmunoprecipitation, yeast two-hybrid, gel shift, and chromatin immunoprecipitation assays) to identify and confirm interaction of Dot1a (the major Dot1l splicing variant in the mouse kidney) with histone deacetylase 2 (HDAC2), as well as the function of the Dot1a-HDAC2 complex in regulating Edn1 transcription. RESULTS In each case, Dot1lAC mice developed more pronounced kidney fibrosis and kidney malfunction compared with wild-type mice. These Dot1lAC phenotypes were ameliorated in the double-knockout DEAC mice. The interaction between Dot1a and HDAC2 prevents the Dot1a-HDAC2 complex from association with DNA, providing a counterbalancing mechanism governing Edn1 transcription by modulating H3 K79 dimethylation and H3 acetylation at the Edn1 promoter. CONCLUSIONS Our study confirms Dot1l to be a genetic and epigenetic modifier of kidney fibrosis, reveals a new mechanism regulating Edn1 transcription by Dot1a and HDAC2, and reinforces endothelin 1 as a therapeutic target of kidney fibrosis.
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Affiliation(s)
- Long Zhang
- Departments of Regenerative and Cancer Cell Biology and
| | - Lihe Chen
- Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, Maryland; and
| | - Chao Gao
- Departments of Regenerative and Cancer Cell Biology and
| | - Enuo Chen
- Departments of Regenerative and Cancer Cell Biology and
| | - Andrea R Lightle
- Pathology and Laboratory Medicine, Albany Medical College, Albany, New York
| | - Llewellyn Foulke
- Pathology and Laboratory Medicine, Albany Medical College, Albany, New York
| | - Bihong Zhao
- Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
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30
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Vaněčková I, Hojná S, Vernerová Z, Kadlecová M, Rauchová H, Kompanowska-Jezierska E, Vaňourková Z, Červenka L, Zicha J. Renoprotection Provided by Additional Diuretic Treatment in Partially Nephrectomized Ren-2 Transgenic Rats Subjected to the Combined RAS and ET A Blockade. Front Physiol 2019; 10:1145. [PMID: 31620007 PMCID: PMC6759492 DOI: 10.3389/fphys.2019.01145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/22/2019] [Indexed: 11/13/2022] Open
Abstract
Objective Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial. Design and Methods Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX. Results At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment. Conclusion A diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).
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Affiliation(s)
- Ivana Vaněčková
- Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Silvie Hojná
- Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Zdenka Vernerová
- Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Michaela Kadlecová
- Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Hana Rauchová
- Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Elzbieta Kompanowska-Jezierska
- Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | | | - Luděk Červenka
- Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Josef Zicha
- Department of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
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31
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Gupta A, Puri S, Puri V. Bioinformatics Unmasks the Maneuverers of Pain Pathways in Acute Kidney Injury. Sci Rep 2019; 9:11872. [PMID: 31417109 PMCID: PMC6695489 DOI: 10.1038/s41598-019-48209-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 07/31/2019] [Indexed: 12/30/2022] Open
Abstract
Acute Kidney injury (AKI) is one of the leading health concerns resulting in accumulation of nitrogenous as well as non-nitrogenous wastes in body and characterised by a rapid deterioration in kidney functions. Besides the major toll from the primary insult in the kidney, consequential extra-renal secondary insults endowed with the pathways of inflammatory milieu often complicates the disease outcome. Some of the known symptoms of AKI leading to clinical reporting are fatigue, loss of appetite, headache, nausea, vomiting, and pain in the flanks, wherein proinflammatory cytokines have been strongly implicated in pathogenesis of AKI and neuro-inflammation. Taking in account these clues, we have tried to decode the neuro-inflammation and pain perception phenomenon during the progression of AKI using the pathway integration and biological network strategies. The pathways and networks were generated using bioinformatics software viz. PANTHER, Genomatix and PathVisio to establish the relationship between immune and neuro related pathway in AKI. These observations envisage a neurol-renal axis that is predicted to involve calcium channels in neuro-inflammatory pathway of AKI. These observations, thus, pave a way for a new paradigm in understanding the interplay of neuro-immunological signalling in AKI.
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Affiliation(s)
- Aprajita Gupta
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
| | - Sanjeev Puri
- Biotechnology Branch UIET, Panjab University, Chandigarh, India
| | - Veena Puri
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India.
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Farrah TE, Anand A, Gallacher PJ, Kimmitt R, Carter E, Dear JW, Mills NL, Webb DJ, Dhaun N. Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease. Hypertension 2019; 74:323-330. [PMID: 31177906 PMCID: PMC6635059 DOI: 10.1161/hypertensionaha.119.12919] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.
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Affiliation(s)
- Tariq E. Farrah
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
| | - Atul Anand
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Peter J. Gallacher
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
| | - Robert Kimmitt
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Edwin Carter
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - James W. Dear
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Nicholas L. Mills
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - David J. Webb
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.)
| | - Neeraj Dhaun
- From the University/British Heart Foundation Centre of Research Excellence, Centre of Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute (T.E.F., A.A., P.J.G., R.K., E.C., J.W.D., N.L.M., D.J.W., N.D.),Department of Renal Medicine, Royal Infirmary of Edinburgh (T.E.F., P.J.G., N.D.)
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Mihanfar A, Sadigh AR, Fattahi A, Latifi Z, Hasanzadeh-Moghadam M, Samadi M, Farzadi L, Hamdi K, Ghasemzadeh A, Nejabati HR, Nouri M. Endothelins and their receptors in embryo implantation. J Cell Biochem 2019; 120:14274-14284. [PMID: 31106465 DOI: 10.1002/jcb.28983] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 03/31/2019] [Accepted: 04/08/2019] [Indexed: 12/12/2022]
Abstract
As a critical stage of pregnancy, the implantation of blastocysts into the endometrium is a progressive, excessively regulated local tissue remodeling step involving a complex sequence of genetic and cellular interplay executed within an optimal time frame. For better understanding the causes of infertility and, more importantly, for developing powerful strategies for successful implantations and combating infertility, an increasing number of recent studies have been focused on the identification and study of newly described substances in the reproductive tree. The endothelins (ET), a 21-aminoacidic family of genes, have been reported to be responsible for the contraction of vascular and nonvascular smooth muscles, including the smooth muscles of the uterus. Therefore, this review aims to comprehensively discuss the physiological role of endothelins and signaling through their receptors, as well as their probable involvement in the implantation process.
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Affiliation(s)
- Aynaz Mihanfar
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Aydin Raei Sadigh
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Fattahi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Latifi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mahrokh Samadi
- Nephrology and Kidney Transplant Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Laya Farzadi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Hamdi
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliyeh Ghasemzadeh
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Nejabati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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Fries JWU. MicroRNAs as markers to monitor endothelin-1 signalling and potential treatment in renal disease: Carcinoma - proteinuric damage - toxicity. Biol Cell 2019; 111:169-186. [PMID: 30866090 DOI: 10.1111/boc.201800059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 01/01/2019] [Accepted: 02/25/2019] [Indexed: 12/11/2022]
Abstract
This review highlights new developments in miRNA as diagnostic and surveillance tools in diseases damaging the renal proximal tubule mediated by endothelin in the field of renal carcinoma, proteinuric kidney disease and tubulotoxicity. A new mechanism in the miRNA regulation of proteins leads to the binding of the miRNA directly to the DNA with premature transcriptional termination and hence the formation of truncated protein isoforms (Mxi2, Vim3). These isoforms are mediated through miRNA15a or miRNA 498, respectively. ET-1 can activate a cytoplasmic complex consisting of NF-κB p65, MAPK p38α, and PKCα. Consequently, PKCα does not transmigrate into the nucleus, which leads to the loss of suppression of a primiRNA15a, maturation of this miRNA in the cytoplasm, tubular secretion and detectability in the urine. This mechanism has been shown in renal cell carcinoma and in proteinuric disease as a biomarker for the activation of the signalling pathway. Similarly, ET-1 induced miRNA 498 transmigrates into the nucleus to form the truncated protein Vim3, which is a biomarker for the benign renal cell tumour, oncocytoma. In tubulotoxicity, ET-1 induced miRNa133a down-regulating multiple-drug-resistant related protein-2, relevant for proteinuric and cisplatin/cyclosporine A toxicity. Current advantages and limitations of miRNAs as urinary biomarkers are discussed.
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Affiliation(s)
- Jochen W U Fries
- Department of Pathology, University Hospital of Koeln, 50931, Koeln, Germany
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Vaněčková I, Hojná S, Kadlecová M, Vernerová Z, Kopkan L, Červenka L, Zicha J. Renoprotective effects of ET(A) receptor antagonists therapy in experimental non-diabetic chronic kidney disease: Is there still hope for the future? Physiol Res 2018; 67:S55-S67. [PMID: 29947528 DOI: 10.33549/physiolres.933898] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.
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Affiliation(s)
- I Vaněčková
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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Vanholder R, Van Laecke S, Glorieux G, Verbeke F, Castillo-Rodriguez E, Ortiz A. Deleting Death and Dialysis: Conservative Care of Cardio-Vascular Risk and Kidney Function Loss in Chronic Kidney Disease (CKD). Toxins (Basel) 2018; 10:E237. [PMID: 29895722 PMCID: PMC6024824 DOI: 10.3390/toxins10060237] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 05/11/2018] [Indexed: 02/07/2023] Open
Abstract
The uremic syndrome, which is the clinical expression of chronic kidney disease (CKD), is a complex amalgam of accelerated aging and organ dysfunctions, whereby cardio-vascular disease plays a capital role. In this narrative review, we offer a summary of the current conservative (medical) treatment options for cardio-vascular and overall morbidity and mortality risk in CKD. Since the progression of CKD is also associated with a higher cardio-vascular risk, we summarize the interventions that may prevent the progression of CKD as well. We pay attention to established therapies, as well as to novel promising options. Approaches that have been considered are not limited to pharmacological approaches but take into account lifestyle measures and diet as well. We took as many randomized controlled hard endpoint outcome trials as possible into account, although observational studies and post hoc analyses were included where appropriate. We also considered health economic aspects. Based on this information, we constructed comprehensive tables summarizing the available therapeutic options and the number and kind of studies (controlled or not, contradictory outcomes or not) with regard to each approach. Our review underscores the scarcity of well-designed large controlled trials in CKD. Nevertheless, based on the controlled and observational data, a therapeutic algorithm can be developed for this complex and multifactorial condition. It is likely that interventions should be aimed at targeting several modifiable factors simultaneously.
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Affiliation(s)
- Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Steven Van Laecke
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Griet Glorieux
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Francis Verbeke
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
| | | | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, 28040 Madrid, Spain.
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Spires D, Poudel B, Shields CA, Pennington A, Fizer B, Taylor L, McPherson KC, Cornelius DC, Williams JM. Prevention of the progression of renal injury in diabetic rodent models with preexisting renal disease with chronic endothelin A receptor blockade. Am J Physiol Renal Physiol 2018; 315:F977-F985. [PMID: 29846112 DOI: 10.1152/ajprenal.00182.2018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The endothelin (ET) system has emerged as a therapeutic target for the treatment of diabetic nephropathy (DN). The present study examined whether chronic endothelin A (ETA) receptor blockade with atrasentan prevents the progression of renal injury in two models of DN with preexisting renal disease that exhibit an increased renal ET-1 system compared with nondiabetic rats: streptozotocin-treated Dahl salt-sensitive (STZ-SS) and type 2 diabetic nephropathy (T2DN) rats. Nine week-old SS rats were treated with (STZ; 50 mg/kg ip) to induce diabetes. After 3 wk of diabetes, proteinuria increased to 353 ± 34 mg/day. The rats were then separated into two groups: 1) vehicle and 2) atrasentan (5 mg·kg-1·day-1) via drinking water. After 6 wk of treatment with atrasentan, mean arterial pressure (MAP) and proteinuria decreased by 12 and 40%, respectively, in STZ-SS rats. The degree of glomerulosclerosis and renal fibrosis was significantly reduced in the kidneys of atrasentan-treated STZ-SS rats compared with vehicle STZ-SS rats. Interestingly, treatment with atrasentan did not affect GFR but significantly increased renal blood flow by 33% and prevented the elevations in filtration fraction and renal vascular resistance by 23 and 20%, respectively, in STZ-SS rats. In contrast to the STZ-SS study, atrasentan had no effect on MAP or proteinuria in T2DN rats. However, treatment with atrasentan significantly decreased glomerular injury and renal fibrosis and prevented the decline in renal function in T2DN rats. These data indicate that chronic ETA blockade produces advantageous changes in renal hemodynamics that slow the progression of renal disease and also reduces renal histopathology in the absence of reducing arterial pressure and proteinuria.
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Affiliation(s)
- Denisha Spires
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Bibek Poudel
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Corbin A Shields
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Alyssa Pennington
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Brianca Fizer
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Lateia Taylor
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Kasi C McPherson
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Denise C Cornelius
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
| | - Jan M Williams
- Departments of Pharmacology and Emergency Medicine, University of Mississippi Medical Center , Jackson, Mississippi
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BISWAS S, FENG B, THOMAS A, CHEN S, AREF-ESHGHI E, SADIKOVIC B, CHAKRABARTI S. Endothelin-1 Regulation Is Entangled in a Complex Web of Epigenetic Mechanisms in Diabetes. Physiol Res 2018; 67:S115-S125. [DOI: 10.33549/physiolres.933836] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5’ UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies.
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Affiliation(s)
| | | | | | | | | | | | - S. CHAKRABARTI
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
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Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel) 2018; 10:33. [PMID: 29316724 PMCID: PMC5793120 DOI: 10.3390/toxins10010033] [Citation(s) in RCA: 221] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 12/21/2017] [Accepted: 12/23/2017] [Indexed: 02/07/2023] Open
Abstract
In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β₂-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.
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Affiliation(s)
- Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
| | - Anneleen Pletinck
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
| | - Eva Schepers
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
| | - Griet Glorieux
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
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Abstract
Over the past 30 years there have been many complementary therapies developed to achieve glycemic control and have an impact on cardiovascular outcomes, as well as reduce the risk of microvascular disease. The 2 most notable new entries have been the sodium-glucose cotransporter 2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) agonists. Both these classes of agents have demonstrated reductions in cardiovascular event rates as well as reductions in blood pressure and weight. Moreover, while both have demonstrated a benefit in slowing nephropathy progression, the SGLT2 inhibitors appear to have a significantly greater effect compared with the GLP-1 agents. There is an ongoing trial specifically powered for renal disease progression, CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy). Additionally, there are 2 other classes of agents being tested to slow nephropathy progression, a selective endothelin-1 receptor antagonist, atrasantan, in the SONAR (Study of Diabetic Nephropathy With Atrasentan) trial and a nonsteroidal mineralocorticoid receptor antagonist, finerenone, in the FIDELIO (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus) trial. These and other studies are discussed.
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Affiliation(s)
- David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - George L Bakris
- Department of Medicine, American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois, USA
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Characterisation of preproendothelin-1 derived peptides identifies Endothelin-Like Domain Peptide as a modulator of Endothelin-1. Sci Rep 2017; 7:4956. [PMID: 28694457 PMCID: PMC5503984 DOI: 10.1038/s41598-017-05365-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/26/2017] [Indexed: 02/06/2023] Open
Abstract
Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal diseases, and in the progression of tumour growth in cancer, but current diagnosis and treatment remain inadequate. Peptides derived from the 212 amino acid precursor preproendothelin-1 (ppET-1) may have utility as biomarkers, or cause biological effects that are unaffected by endothelin receptor antagonists. Here, we used specific immunoassays and LC-MS/MS to identify NT-proET-1 (ppET-1[18–50]), Endothelin-Like Domain Peptide (ELDP, ppET-1[93–166]) and CT-proET-1 (ppET-1[169–212]) in conditioned media from cultured endothelial cells. Synthesis of these peptides correlated with ET-1, and plasma ELDP and CT-proET-1 were elevated in patients with chronic heart failure. Clearance rates of NT-proET-1, ELDP and CT-proET-1 were determined after i.v. injection in anaesthetised rats. CT-proET-1 had the slowest systemic clearance, hence providing a biological basis for it being a better biomarker of ET-1 synthesis. ELDP contains the evolutionary conserved endothelin-like domain sequence, which potentially confers biological activity. On isolated arteries ELDP lacked direct vasoconstrictor effects. However, it enhanced ET-1 vasoconstriction and prolonged the increase in blood pressure in anaesthetised rats. ELDP may therefore contribute to disease pathogenesis by augmenting ET-1 responses.
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Hunter RW, Moorhouse R, Farrah TE, MacIntyre IM, Asai T, Gallacher PJ, Kerr D, Melville V, Czopek A, Morrison EE, Ivy JR, Dear JW, Bailey MA, Goddard J, Webb DJ, Dhaun N. First-in-Man Demonstration of Direct Endothelin-Mediated Natriuresis and Diuresis. Hypertension 2017; 70:192-200. [PMID: 28507171 PMCID: PMC5739104 DOI: 10.1161/hypertensionaha.116.08832] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 12/19/2016] [Accepted: 04/19/2017] [Indexed: 01/23/2023]
Abstract
Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension, but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ETB receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation/blockade. We aimed to determine the effects of ET signaling on salt transport in the human nephron by administering subpressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. After sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (≤300 pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (≈8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium-potassium-chloride cotransporter (NKCC2) in urinary extracellular vesicles. Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by coprescribing potassium-sparing diuretics.
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Affiliation(s)
- Robert W Hunter
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Rebecca Moorhouse
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Tariq E Farrah
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Iain M MacIntyre
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Takae Asai
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Peter J Gallacher
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Debbie Kerr
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Vanessa Melville
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Alicja Czopek
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Emma E Morrison
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Jess R Ivy
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - James W Dear
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Matthew A Bailey
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Jane Goddard
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - David J Webb
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Neeraj Dhaun
- From the British Heart Foundation Centre of Research Excellence and The Queen's Medical Research Institute, University of Edinburgh, United Kingdom.
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Ilyas Z, Chaiban JT, Krikorian A. Novel insights into the pathophysiology and clinical aspects of diabetic nephropathy. Rev Endocr Metab Disord 2017; 18:21-28. [PMID: 28289965 DOI: 10.1007/s11154-017-9422-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Diabetic nephropathy (DN) is a well-described complication of diabetes mellitus and the leading cause of end stage renal disease (ESRD). Although increased albuminuria has been the gold standard for screening, data suggests that renal damage starts long before the onset of clinically apparent increases in macro and even micro-albuminuria. Clinical practice guidelines for the prevention of DN have been traditionally focused on the control of serum glucose, blood pressure and dyslipidemia, with some focus on the renin-angiotensin-aldosterone system (RAAS) as a main target for successful therapy. Recent evidence has led to a better understanding of the underlying mechanisms of the pathophysiology of this disease and suggests that various novels pathways can be targeted to delay and even prevent the progression of DN. Hence a more comprehensive therapeutic approach to therapy is on the horizon, carrying the promise for a more successful and impactful management. This review will highlight new insights into the pathophysiology, clinical aspects and future diagnostic and therapeutic modalities for DN.
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Affiliation(s)
- Zubair Ilyas
- Department of Internal Medicine, University of Illinois at Chicago, Advocate Christ Medical Center, Chicago, IL, USA
| | - Joumana T Chaiban
- Department of Internal Medicine, University of Illinois at Chicago, Advocate Christ Medical Center, Chicago, IL, USA
- Division of Endocrinology, Advocate Christ Medical Center, Chicago, IL, USA
| | - Armand Krikorian
- Department of Internal Medicine, University of Illinois at Chicago, Advocate Christ Medical Center, Chicago, IL, USA.
- Division of Endocrinology, Advocate Christ Medical Center, Chicago, IL, USA.
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Aschauer C, Perco P, Heinzel A, Sunzenauer J, Oberbauer R. Positioning of Tacrolimus for the Treatment of Diabetic Nephropathy Based on Computational Network Analysis. PLoS One 2017; 12:e0169518. [PMID: 28060893 PMCID: PMC5217951 DOI: 10.1371/journal.pone.0169518] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/19/2016] [Indexed: 01/15/2023] Open
Abstract
Objective To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies.
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Affiliation(s)
| | - Paul Perco
- Emergentec Biodevelopment GmbH, Vienna, Austria
- Department of Internal Medicine IV, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Judith Sunzenauer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Rainer Oberbauer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
- * E-mail:
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Pan Y, Hu C, Chen PH, Gu YH, Qiao QY, Pan LH, Zhou DC, Gu HF, Fu SK, Jin HM. Association of oral endothelin receptor antagonists with risks of cardiovascular events and mortality: meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 2016; 73:267-278. [PMID: 27957707 DOI: 10.1007/s00228-016-2171-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/30/2016] [Indexed: 10/24/2022]
Abstract
BACKGROUND Endothelin receptor antagonists (ERAs) are widely used in a variety of disorders, including pulmonary artery hypertension, systemic sclerosis, diabetic and kidney diseases, and several tumors. However, reported adverse events, especially increased risks of cardiovascular disease (CVD) morbidity and mortality, have cast doubt on their potential clinical application. Therefore, we conducted this meta-analysis to confirm whether ERAs increased CVD risk and mortality. METHODS We systematically searched PubMed (1966-2015), EMBASE (1974-2015), ClinicalTrials.gov, and the Cochrane Controlled Clinical Trials Register Database for randomized controlled trials published between Jan 1, 1990 and Mar 18, 2015. Inclusion criteria included a study duration of more than 3 weeks, the use of a randomized control group receiving an oral ERA or placebo, and the availability of outcome data for cardiovascular events and all-cause death. RESULTS A total of 33 trials met the inclusion criteria. There were 8098 cases in the ERA group and 5074 cases in the placebo group. Compared with the control group, the risk ratio (RR) for all-cause death in the ERA group was 0.983 [95% confidence interval (CI), 0.883 to 1.094, P = 0.754]. The summary RR for cardiovascular events was 1.651 in the ERA group (95% CI, 1.164 to 2.34, P = 0.005). The pooled results showed that ERAs treatment could lead to more edema, anemia, and abnormal transaminase levels. Also, there was an increased proportion of discontinued therapy in the ERA treatment because of side effects (RR = 1.322, 95% CI, 1.036 to 1.686, P = 0.025). There were no significant differences in the experienced episodes of headache and dyspnea between the active therapy and control groups. CONCLUSIONS ERAs therapy is not significantly associated with increased all-cause death, but there are more cardiovascular events and edema or fluid retention, anemia, and liver enzymes disorder. Large clinical randomized controlled studies are needed to further confirm the safety of the clinical application of ERAs.
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Affiliation(s)
- Yu Pan
- Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Chun Hu
- Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Pei Hua Chen
- Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yan Hong Gu
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Qing Yan Qiao
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Li Hua Pan
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Dong Chi Zhou
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Hui Fang Gu
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Shun Kun Fu
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China
| | - Hui Min Jin
- Division of Nephrology, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai, 201399, China.
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Heimlich JB, Speed JS, O'Connor PM, Pollock JS, Townes TM, Meiler SE, Kutlar A, Pollock DM. Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol 2016; 173:386-95. [PMID: 26561980 DOI: 10.1111/bph.13380] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/16/2015] [Accepted: 10/25/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND PURPOSE Endothelin-1 (ET-1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET-1 acting via the ETA receptor contributes to renal injury in a mouse model of sickle cell disease. EXPERIMENTAL APPROACH Adult, humanized HbSS (homozygous for sickle Hb) mice had increased ET-1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ETA receptor mRNA expression was also elevated in HbSS (sickle) mice although ETB receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ETA receptors in the renal vascular tissue when compared with control mice. KEY RESULTS In response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ETA antagonist, ABT-627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT-627. Finally, ETA receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease. CONCLUSIONS AND IMPLICATIONS These data support a novel role for ET-1 in the progression of sickle nephropathy, specifically via the ETA receptor, and suggest a potential role for ETA receptor antagonism in a treatment strategy.
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Affiliation(s)
- J Brett Heimlich
- 1epartment of Physiology, Augusta University, Augusta, GA 30912, USA
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Kamal FA, Travers JG, Schafer AE, Ma Q, Devarajan P, Blaxall BC. G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure. J Am Soc Nephrol 2016; 28:197-208. [PMID: 27297948 DOI: 10.1681/asn.2015080852] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 04/08/2016] [Indexed: 12/13/2022] Open
Abstract
Development of CKD secondary to chronic heart failure (CHF), known as cardiorenal syndrome type 2 (CRS2), clinically associates with organ failure and reduced survival. Heart and kidney damage in CRS2 results predominantly from chronic stimulation of G protein-coupled receptors (GPCRs), including adrenergic and endothelin (ET) receptors, after elevated neurohormonal signaling of the sympathetic nervous system and the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein βγ-subunit (Gβγ), GPCR-kinase 2, and β-arrestin are central to various cardiovascular diseases, the role of such alterations in kidney diseases remains largely unknown. We investigated the possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC). By 12 weeks after TAC, mice developed CKD secondary to CHF associated with elevated renal GPCR-Gβγ signaling and ET system expression. Notably, systemic pharmacologic Gβγ inhibition by gallein, which we previously showed alleviates CHF in this model, attenuated these pathologic renal changes. To investigate a direct effect of gallein on the kidney, we used a bilateral ischemia-reperfusion AKI mouse model, in which gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET system activation. Furthermore, in vitro studies showed a key role for ET receptor-Gβγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gβγ in AKI and suggest GPCR-Gβγ inhibition as a novel therapeutic approach for treating CRS2 and AKI.
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Affiliation(s)
- Fadia A Kamal
- The Heart Institute, Molecular Cardiovascular Biology and
| | | | | | - Qing Ma
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Prasad Devarajan
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Schievink B, de Zeeuw D, Smink PA, Andress D, Brennan JJ, Coll B, Correa-Rotter R, Hou FF, Kohan D, Kitzman DW, Makino H, Parving HH, Perkovic V, Remuzzi G, Tobe S, Toto R, Hoekman J, Lambers Heerspink HJ. Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers. Eur J Prev Cardiol 2016; 23:758-68. [PMID: 26229089 PMCID: PMC7735387 DOI: 10.1177/2047487315598709] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 07/13/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. DESIGN We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. METHODS We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. RESULTS The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. CONCLUSIONS Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.
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Affiliation(s)
- Bauke Schievink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Paul A Smink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
| | | | | | - Blai Coll
- Renal Clinical Development, Abbvie, North Chicago, USA
| | - Ricardo Correa-Rotter
- National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico
| | - Fan Fan Hou
- Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Donald Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA
| | - Dalane W Kitzman
- Cardiology Section, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, USA
| | | | - Hans-Henrik Parving
- Department of Medical Endocrinology Rigshospitalet, University Hospital of Copenhagen, Denmark
| | - Vlado Perkovic
- The George Institute for International Health, The University of Sydney, Australia
| | - Giuseppe Remuzzi
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Bergamo, Italy; Unit of Nephrology, Dialysis and Transplantation, AO Papa Giovanni XXIII, Bergamo, Italy
| | - Sheldon Tobe
- Sunnybrook Health Sciences Center, Toronto, Canada
| | - Robert Toto
- University of Texas Southwestern Medical Center, Dallas, USA
| | - Jarno Hoekman
- Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands
| | - Hiddo J Lambers Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands
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Quiroga B, Arroyo D, de Arriba G. Present and future in the treatment of diabetic kidney disease. J Diabetes Res 2015; 2015:801348. [PMID: 25945357 PMCID: PMC4405221 DOI: 10.1155/2015/801348] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 03/26/2015] [Accepted: 03/27/2015] [Indexed: 12/21/2022] Open
Abstract
Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade.
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Affiliation(s)
- Borja Quiroga
- Nephrology Unit, Hospital Universitario de Guadalajara, Spain
| | - David Arroyo
- Nephrology Unit, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - Gabriel de Arriba
- Nephrology Unit, Hospital Universitario de Guadalajara, Spain
- Medicine and Medicine Specialities Department, Universidad de Alcalá (UAH), Madrid, Spain
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Dhaun N, Yuzugulen J, Kimmitt RA, Wood EG, Chariyavilaskul P, MacIntyre IM, Goddard J, Webb DJ, Corder R. Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism. J Am Heart Assoc 2015; 4:e001624. [PMID: 25801761 PMCID: PMC4392442 DOI: 10.1161/jaha.114.001624] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background Endothelin 1 (ET‐1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET‐1 peptides, endothelin‐like domain peptide (ELDP) and C‐terminal pro‐ET‐1 (CT‐proET‐1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists. Methods and Results We assessed plasma and urine ELDP and plasma CT‐proET‐1 in CKD patients with minimal comorbidity. Next, in a randomized double‐blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT‐proET‐1 increased with CKD stage (both P<0.0001), correlating inversely with estimated glomerular filtration rate (both P<0.0001). Following intervention, placebo and nifedipine did not affect plasma and urine ELDP or plasma CT‐proET‐1. Sitaxentan increased both plasma ELDP and CT‐proET‐1 (baseline versus week 6±SEM: ELDP, 11.8±0.5 versus 13.4±0.6 fmol/mL; CT‐proET‐1, 20.5±1.2 versus 23.3±1.5 fmol/mL; both P<0.0001). Plasma ET‐1 was unaffected by any treatment. Following sitaxentan, plasma ELDP and CT‐proET‐1 correlated negatively with 24‐hour urinary sodium excretion. Conclusions ELDP and CT‐proET‐1 increase in CKD and thus are potentially useful biomarkers of renal injury. Increases in response to endothelin A antagonism may reflect EDN1 upregulation, which may partly explain fluid retention with these agents. Clinical Trial Registration URL: www.clinicalTrials.gov Unique identifier: NCT00810732
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Affiliation(s)
- Neeraj Dhaun
- BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.) Department of Renal Medicine, Royal Infirmary of Edinburgh, UK (N.D., J.G.)
| | - Jale Yuzugulen
- William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.)
| | - Robert A Kimmitt
- BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.)
| | - Elizabeth G Wood
- William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.)
| | - Pajaree Chariyavilaskul
- BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.)
| | - Iain M MacIntyre
- BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.)
| | - Jane Goddard
- Department of Renal Medicine, Royal Infirmary of Edinburgh, UK (N.D., J.G.)
| | - David J Webb
- BHF Centre of Research Excellence, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK (N.D., R.A.K., P.C., I.M.M.I., D.J.W.)
| | - Roger Corder
- William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, UK (J.Y., E.G.W., R.C.)
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