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1
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Liu M, Chen J, Sun M, Zhang L, Yu Y, Mi W, Ma Y, Wang G. Protection of Ndrg2 deficiency on renal ischemia-reperfusion injury via activating PINK1/Parkin-mediated mitophagy. Chin Med J (Engl) 2024; 137:2603-2614. [PMID: 38407220 PMCID: PMC11556958 DOI: 10.1097/cm9.0000000000002957] [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: 11/04/2023] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Renal ischemia-reperfusion (R-I/R) injury is the most prevalent cause of acute kidney injury, with high mortality and poor prognosis. However, the underlying pathological mechanisms are not yet fully understood. Therefore, this study aimed to investigate the role of N-myc downstream-regulated gene 2 ( Ndrg2 ) in R-I/R injury. METHODS We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining, real-time polymerase chain reaction, and western blotting. We then detected R-I/R injury in Ndrg2-deficient ( Ndrg2-/- ) mice and wild type ( Ndrg2+/+ ) littermates in vivo , and detected oxygen and glucose deprivation and reperfusion (OGD-R) injury in HK-2 cells. We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining, biochemical assays, and western blot. Finally, we measured the levels of mitophagy in Ndrg2+/+ and Ndrg2-/- mice after R-I/R injury or HK-2 cells in OGD-R injury. RESULTS Ndrg2 was primarily expressed in renal proximal tubules and its expression was significantly decreased 24 h after R-I/R injury. Ndrg2-/- mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+ mice. Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways, downregulated inflammatory responses and oxidative stress, and increased autophagy following R-I/R injury. Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage. Notably, Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury, increased the expression of heme oxygenase-1, decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, and increased the expression of the PINK1/Parkin pathway. CONCLUSION Ndrg2 deficiency might become a therapy target for R-I/R injury by decreasing oxidative stress, maintaining mitochondrial homeostasis, and activating PINK1/Parkin-mediated mitophagy.
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Affiliation(s)
- Min Liu
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Jianwen Chen
- Department of Nephrology, The First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
| | - Miao Sun
- Department of Anesthesiology, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning 121000, China
| | - Lixia Zhang
- Department of Burn and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, China
| | - Yao Yu
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Weidong Mi
- Department of Anesthesiology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yulong Ma
- Department of Anesthesiology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Guyan Wang
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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2
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Lv L, Liu Y, Xiong J, Wang S, Li Y, Zhang B, Huang Y, Zhao J. Role of G protein coupled receptors in acute kidney injury. Cell Commun Signal 2024; 22:423. [PMID: 39223553 PMCID: PMC11367933 DOI: 10.1186/s12964-024-01802-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Acute kidney injury (AKI) is a clinical condition characterized by a rapid decline in kidney function, which is associated with local inflammation and programmed cell death in the kidney. The G protein-coupled receptors (GPCRs) represent the largest family of signaling transduction proteins in the body, and approximately 40% of drugs on the market target GPCRs. The expressions of various GPCRs, prostaglandin receptors and purinergic receptors, to name a few, are significantly altered in AKI models. And the role of GPCRs in AKI is catching the eyes of researchers due to their distinctive biological functions, such as regulation of hemodynamics, metabolic reprogramming, and inflammation. Therefore, in this review, we aim to discuss the role of GPCRs in the pathogenesis of AKI and summarize the relevant clinical trials involving GPCRs to assess the potential of GPCRs and their ligands as therapeutic targets in AKI and the transition to AKI-CKD.
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Affiliation(s)
- Liangjing Lv
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Yong Liu
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Jiachuan Xiong
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Shaobo Wang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Yan Li
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Bo Zhang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Yinghui Huang
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China
| | - Jinghong Zhao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University, Third Military Medical University), Chongqing, 400037, China.
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3
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Huang X, Chorianopoulou A, Kalkounou P, Georgiou M, Pousias A, Davies A, Pearce A, Harris M, Lambrinidis G, Marakos P, Pouli N, Kolocouris A, Lougiakis N, Ladds G. Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor. J Med Chem 2024; 67:13117-13146. [PMID: 39073853 PMCID: PMC11320584 DOI: 10.1021/acs.jmedchem.4c01092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/18/2024] [Accepted: 07/01/2024] [Indexed: 07/30/2024]
Abstract
Antagonism of the human adenosine A3 receptor (hA3R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA3R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA3R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA3R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA3R antagonist.
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Affiliation(s)
- Xianglin Huang
- Department
of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
| | - Anna Chorianopoulou
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Panagoula Kalkounou
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Maria Georgiou
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Athanasios Pousias
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Amy Davies
- Department
of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
| | - Abigail Pearce
- Department
of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
| | - Matthew Harris
- Department
of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
| | - George Lambrinidis
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Panagiotis Marakos
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Nicole Pouli
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Antonios Kolocouris
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Nikolaos Lougiakis
- Laboratory
of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department
of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou 15771, Athens, Greece
| | - Graham Ladds
- Department
of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K.
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4
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Stryjak I, Warmuzińska N, Łuczykowski K, Jaroch K, Urbanellis P, Selzner M, Bojko B. Metabolomic and lipidomic landscape of porcine kidney associated with kidney perfusion in heart beating donors and donors after cardiac death. Transl Res 2024; 267:79-90. [PMID: 38052298 DOI: 10.1016/j.trsl.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 10/23/2023] [Accepted: 12/01/2023] [Indexed: 12/07/2023]
Abstract
Transplant centers are currently facing a lack of tools to ensure adequate evaluation of the quality of the available organs, as well as a significant shortage of kidney donors. Therefore, efforts are being made to facilitate the effective use of available organs and expand the donor pool, particularly with expanded criteria donors. Fulfilling a need, we aim to present an innovative analytical method based on solid-phase microextraction (SPME) - chemical biopsy. In order to track changes affecting the organ throughout the entire transplant procedure, porcine kidneys were subjected to multiple samplings at various time points. The application of small-diameter SPME probes assured the minimal invasiveness of the procedure. Porcine model kidney autotransplantation was executed for the purpose of simulating two types of donor scenarios: donors with a beating heart (HBD) and donors after cardiac death (DCD). All renal grafts were exposed to continuous normothermic ex vivo perfusion. Following metabolomic and lipidomic profiling using high-performance liquid chromatography coupled to a mass spectrometer, we observed differences in the profiles of HBD and DCD kidneys. The alterations were predominantly related to energy and glucose metabolism, and differences in the levels of essential amino acids, purine nucleosides, lysophosphocholines, phosphoethanolamines, and triacylglycerols were noticed. Our results indicate the potential of implementing chemical biopsy in the evaluation of graft quality and monitoring of renal function during perfusion.
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Affiliation(s)
- Iga Stryjak
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Karol Jaroch
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Peter Urbanellis
- Ajmera Transplant Center, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Markus Selzner
- Ajmera Transplant Center, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada; Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
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5
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Raikou VD. Renoprotective strategies. World J Nephrol 2024; 13:89637. [PMID: 38596266 PMCID: PMC11000037 DOI: 10.5527/wjn.v13.i1.89637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/01/2023] [Accepted: 12/26/2023] [Indexed: 03/22/2024] Open
Abstract
Kidney disease remains a condition with an increasing incidence, high morbidity and mortality associated with cardiovascular events. The incidence of end-stage renal disease is expected to increase. Despite of the technical improvement, dialysis never achieved a full clearance of the blood dialysis. Therefore, the demand for new renoprotective measures has never been greater. Here, we report new strategies for preventing renal damage.
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Affiliation(s)
- Vaia D Raikou
- Department of Nephrology, Doctors’General Clinic, Athens 11257, Greece
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6
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Federico S, Persico M, Trevisan L, Biasinutto C, Bolcato G, Salmaso V, Da Ros T, Gianferrara T, Prencipe F, Kachler S, Klotz KN, Pacor S, Moro S, Spalluto G. [1,2,4]Triazolo[1,5-c]pyrimidines as Tools to Investigate A 3 Adenosine Receptors in Cancer Cell Lines. ChemMedChem 2023; 18:e202300299. [PMID: 37675643 DOI: 10.1002/cmdc.202300299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/31/2023] [Accepted: 09/06/2023] [Indexed: 09/07/2023]
Abstract
The A3 adenosine receptor is an interesting target whose role in cancer is controversial. In this work, a structural investigation at the 2-position of the [1,2,4]triazolo[1,5-c]pyrimidine nucleus was performed, finding new potent and selective A3 adenosine receptor antagonists such as the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (20, DZ123) that showed a Ki value of 0.47 nM and an exceptional selectivity profile over the other adenosine receptor subtypes. Computational studies were performed to rationalize the affinity and the selectivity profile of the tested compounds at the A3 adenosine receptor and the A1 and A2A adenosine receptors. Compound 20 was tested on both A3 adenosine receptor positive cell lines (CHO-A3 AR transfected, THP1 and HCT16) and on A3 negative cancer cell lines, showing no effect in the latter and a pro-proliferative effect at a low concentration in the former. These interesting results pave the way to further investigation on both the mechanism involved and potential therapeutic applications.
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Affiliation(s)
- Stephanie Federico
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Margherita Persico
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Letizia Trevisan
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Chiara Biasinutto
- Department of Life Sciences, University of Trieste, Via Licio Giorgieri 5, 34127, Trieste, Italy
| | - Giovanni Bolcato
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131, Padova, Italy
| | - Veronica Salmaso
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131, Padova, Italy
| | - Tatiana Da Ros
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Teresa Gianferrara
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Filippo Prencipe
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
| | - Sonja Kachler
- Rudolf-Virchow-Zentrum -, Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany
| | - Karl-Norbert Klotz
- Institut für Pharmakologie und Toxikologie, University of Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany
| | - Sabrina Pacor
- Department of Life Sciences, University of Trieste, Via Licio Giorgieri 5, 34127, Trieste, Italy
| | - Stefano Moro
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131, Padova, Italy
| | - Giampiero Spalluto
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127, Trieste, Italy
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7
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Wang P, Gao R, Wu T, Zhang J, Sun X, Fan F, Wang C, Qian S, Li B, Zou Y, Huo Y, Fassett J, Chen Y, Ge J, Sun A. Accumulation of endogenous adenosine improves cardiomyocyte metabolism via epigenetic reprogramming in an ischemia-reperfusion model. Redox Biol 2023; 67:102884. [PMID: 37725888 PMCID: PMC10507380 DOI: 10.1016/j.redox.2023.102884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/30/2023] [Accepted: 09/10/2023] [Indexed: 09/21/2023] Open
Abstract
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
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Affiliation(s)
- Peng Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Rifeng Gao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Cardiac Surgery Department, The Second Affiliated Hospital Zhejiang University School of Medicine, China
| | - Tingting Wu
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jinyan Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaolei Sun
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fan Fan
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cong Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sanli Qian
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bingyu Li
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuqing Huo
- Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - John Fassett
- Department of Pharmacology and Toxicology, University of Graz, 8010, Graz, Austria
| | - Yingjie Chen
- Department of Physiology & Biophysics, University Mississippi Medical Center, MS, 39216, USA
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Aijun Sun
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
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8
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Groves AM, Johnston CJ, Beutner G, Dahlstrom JE, Koina M, O'Reilly M, Marples B, Porter G, Brophy PD, Kent AL. Effects of photobiomodulation and caffeine treatment on acute kidney injury in a hypoxic ischemic neonatal rat model. Physiol Rep 2023; 11:e15773. [PMID: 37549967 PMCID: PMC10406568 DOI: 10.14814/phy2.15773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/06/2023] [Accepted: 07/06/2023] [Indexed: 08/09/2023] Open
Abstract
Hypoxic ischemic encephalopathy (HIE) occurs in 2-5/1000 births, with acute kidney injury (AKI) occurring in 40%. AKI increases morbidity and mortality. Caffeine, an adenosine receptor antagonist, and photobiomodulation (PBM), working on cytochrome c oxidase, are potential treatments for AKI. To examine effects of caffeine and PBM on AKI in rats, Day 7 pups underwent a HIE intervention (Modified Rice-Vannucci model) replicating pathology observed in humans. Caffeine was administered for 3 days and/or PBM for 5 days following HIE. Weights and urine for biomarkers (NGAL, albumin, KIM-1, osteopontin) were collected prior to HIE, daily post intervention and at sacrifice. Both treatments reduced kidney injury seen on electron microscopy, but not when combined. HIE elevated urinary NGAL and albumin on Days 1-3 post-HIE, before returning to control levels. This elevation was significantly reduced by PBM or caffeine. KIM-1 was significantly elevated for 7 days post-HIE and was reduced by both treatments. Osteopontin was not altered by HIE or the treatments. Treatments, individually but not in combination, improved HIE-induced reductions in the enzymatic activity of mitochondrial complexes II-III. PBM and caffeine also improved weight gain. PBM and caffeine reduces AKI diagnosed by urinary biomarkers and confirmed by EM findings.
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Affiliation(s)
- A. M. Groves
- Department of Radiation OncologyUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - C. J. Johnston
- Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - G. Beutner
- Department of Pediatrics, Division of CardiologyUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - J. E. Dahlstrom
- Department of Anatomical PathologyCanberra HospitalWodenAustralian Capital TerritoryAustralia
- College of Health and Medicine, Australian National UniversityCanberraAustralian Capital TerritoryAustralia
| | - M. Koina
- Department of Anatomical PathologyCanberra HospitalWodenAustralian Capital TerritoryAustralia
- College of Health and Medicine, Australian National UniversityCanberraAustralian Capital TerritoryAustralia
| | - M. O'Reilly
- Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - B. Marples
- Department of Radiation OncologyUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - G. Porter
- Department of Pediatrics, Division of CardiologyUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - P. D. Brophy
- Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
| | - A. L. Kent
- Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterNew YorkUSA
- College of Health and Medicine, Australian National UniversityCanberraAustralian Capital TerritoryAustralia
- Department of Neonatology, Women's and Babies DivisionWomen's and Children's HospitalAdelaideSouth AustraliaAustralia
- University of Adelaide, School of MedicineAdelaideSouth AustraliaAustralia
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9
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Stampelou M, Suchankova A, Tzortzini E, Dhingra L, Barkan K, Lougiakis N, Marakos P, Pouli N, Ladds G, Kolocouris A. Dual A1/A3 Adenosine Receptor Antagonists: Binding Kinetics and Structure-Activity Relationship Studies Using Mutagenesis and Alchemical Binding Free Energy Calculations. J Med Chem 2022; 65:13305-13327. [PMID: 36173355 DOI: 10.1021/acs.jmedchem.2c01123] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Drugs targeting adenosine receptors (AR) can provide treatment for diseases. We report the identification of 7-(phenylamino)-pyrazolo[3,4-c]pyridines L2-L10, A15, and A17 as low-micromolar to low-nanomolar A1R/A3R dual antagonists, with 3-phenyl-5-cyano-7-(trimethoxyphenylamino)-pyrazolo[3,4-c]pyridine (A17) displaying the highest affinity at both receptors with a long residence time of binding, as determined using a NanoBRET-based assay. Two binding orientations of A17 produce stable complexes inside the orthosteric binding area of A1R in molecular dynamics (MD) simulations, and we selected the most plausible orientation based on the agreement with alanine mutagenesis supported by affinity experiments. Interestingly, for drug design purposes, the mutation of L2506.51 to alanine increased the binding affinity of A17 at A1R. We explored the structure-activity relationships against A1R using alchemical binding free energy calculations with the thermodynamic integration coupled with the MD simulation (TI/MD) method, applied on the whole G-protein-coupled receptor-membrane system, which showed a good agreement (r = 0.73) between calculated and experimental relative binding free energies.
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Affiliation(s)
- Margarita Stampelou
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
| | - Anna Suchankova
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K
| | - Efpraxia Tzortzini
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
| | - Lakshiv Dhingra
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K
| | - Kerry Barkan
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K
| | - Nikolaos Lougiakis
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
| | - Panagiotis Marakos
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
| | - Nicole Pouli
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
| | - Graham Ladds
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, U.K
| | - Antonios Kolocouris
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, 15771 Athens, Greece
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10
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CD73-Adenosinergic Axis Mediates the Protective Effect of Extracellular Vesicles Derived from Mesenchymal Stromal Cells on Ischemic Renal Damage in a Rat Model of Donation after Circulatory Death. Int J Mol Sci 2022; 23:ijms231810681. [PMID: 36142593 PMCID: PMC9501320 DOI: 10.3390/ijms231810681] [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: 08/11/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/21/2022] Open
Abstract
We propose a new organ-conditioning strategy based on mesenchymal stromal cell (MSCs)/extracellular vesicle (EVs) delivery during hypothermic perfusion. MSCs/EVs marker CD73 is present on renal proximal tubular cells, and it protects against renal ischemia-reperfusion injury by converting adenosine monophosphate into adenosine (ADO). In this study, after checking if CD73-silenced EVs (EVsi) would impact in vitro tubular-cell proliferation, we perfused kidneys of a rat model of donation after circulatory death, with Belzer solution (BS) alone, BS supplemented with MSCs, EVs, or EVsi. The ADO and ATP levels were measured in the effluents and tissues. Global renal ischemic damage score (GRS), and tubular cell proliferation index (IPT) were evaluated in the tissue. EVsi did not induce cell proliferation in vitro. Ex vivo kidneys perfused with BS or BS + EVsi showed the worst GRS and higher effluent ADO levels than the MSC- and EV-perfused kidneys. In the EV-perfused kidneys, the tissue and effluent ATP levels and IPT were the highest, but not if CD73 was silenced. Tissue ATP content was positively correlated with tissue ADO content and negatively correlated with effluent ADO level in all groups. In conclusion, kidney conditioning with EVs protects against ischemic damage by activating the CD73/ADO system.
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11
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Mahmood A, Iqbal J. Purinergic receptors modulators: An emerging pharmacological tool for disease management. Med Res Rev 2022; 42:1661-1703. [PMID: 35561109 DOI: 10.1002/med.21888] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/16/2022] [Accepted: 05/04/2022] [Indexed: 11/10/2022]
Abstract
Purinergic signaling is mediated through extracellular nucleotides (adenosine 5'-triphosphate, uridine-5'-triphosphate, adenosine diphosphate, uridine-5'-diphosphate, and adenosine) that serve as signaling molecules. In the early 1990s, purines and pyrimidine receptors were cloned and characterized drawing the attention of scientists toward this aspect of cellular signaling. This signaling pathway is comprised of four subtypes of adenosine receptors (P1), eight subtypes of G-coupled protein receptors (P2YRs), and seven subtypes of ligand-gated ionotropic receptors (P2XRs). In current studies, the pathophysiology and therapeutic potentials of these receptors have been focused on. Various ligands, modulating the functions of purinergic receptors, are in current clinical practices for the treatment of various neurodegenerative disorders and cardiovascular diseases. Moreover, several purinergic receptors ligands are in advanced phases of clinical trials as a remedy for depression, epilepsy, autism, osteoporosis, atherosclerosis, myocardial infarction, diabetes, irritable bowel syndrome, and cancers. In the present study, agonists and antagonists of purinergic receptors have been summarized that may serve as pharmacological tools for drug design and development.
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Affiliation(s)
- Abid Mahmood
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad, Pakistan
| | - Jamshed Iqbal
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad, Pakistan
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12
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Cooper SL, Wragg ES, Pannucci P, Soave M, Hill SJ, Woolard J. Regionally selective cardiovascular responses to adenosine A 2A and A 2B receptor activation. FASEB J 2022; 36:e22214. [PMID: 35230706 PMCID: PMC9415116 DOI: 10.1096/fj.202101945r] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/31/2022] [Accepted: 02/07/2022] [Indexed: 11/25/2022]
Abstract
Adenosine is a local mediator that regulates changes in the cardiovascular system via activation of four G protein-coupled receptors (A1 , A2A , A2B , A3 ). Here, we have investigated the effect of A2A and A2B -selective agonists on vasodilatation in three distinct vascular beds of the rat cardiovascular system. NanoBRET ligand binding studies were used to confirm receptor selectivity. The regional hemodynamic effects of adenosine A2A and A2B selective agonists were investigated in conscious rats. Male Sprague-Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes on the renal artery, mesenteric artery, and the descending abdominal aorta. Cardiovascular responses were measured following intravenous infusion (3 min for each dose) of the A2A -selective agonist CGS 21680 (0.1, 0.3, 1 µg kg-1 min-1 ) or the A2B -selective agonist BAY 60-6583 (4,13.3, 40 µg kg-1 min-1 ) following predosing with the A2A -selective antagonist SCH 58261 (0.1 or 1 mg kg-1 min-1 ), the A2B /A2A antagonist PSB 1115 (10 mg kg-1 min-1 ) or vehicle. The A2A -selective agonist CGS 21680 produced a striking increase in heart rate (HR) and hindquarters vascular conductance (VC) that was accompanied by a significant decrease in mean arterial pressure (MAP) in conscious rats. In marked contrast, the A2B -selective agonist BAY 60-6583 significantly increased HR and VC in the renal and mesenteric vascular beds, but not in the hindquarters. Taken together, these data indicate that A2A and A2B receptors are regionally selective in their regulation of vascular tone. These results suggest that the development of A2B receptor agonists to induce vasodilatation in the kidney may provide a good therapeutic approach for the treatment of acute kidney injury.
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Affiliation(s)
- Samantha L. Cooper
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
| | - Edward S. Wragg
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
| | - Patrizia Pannucci
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
| | - Mark Soave
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
| | - Stephen J. Hill
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
| | - Jeanette Woolard
- Division of Physiology, Pharmacology and NeuroscienceSchool of Life SciencesUniversity of NottinghamNottinghamUK,Centre of Membrane Proteins and ReceptorsUniversity of Birmingham and University of NottinghamMidlandsUK
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13
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Xue J, Zhu K, Cao P, Long C, Deng Y, Liu T, Yin G, Li X, Wang Z. Ischemic preconditioning-induced protective effect for promoting angiogenesis in renal ischemia-reperfusion injury by regulating miR-376c-3p/HIF-1α/VEGF axis in male rats. Life Sci 2022; 299:120357. [PMID: 35092734 DOI: 10.1016/j.lfs.2022.120357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 01/23/2022] [Accepted: 01/23/2022] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Ischemic preconditioning (IPC) is defined as a well-established phenomenon in which brief exposure to sublethal episodes of ischemia and reperfusion induces a tolerance to injurious effects of prolonged ischemia by exploiting intrinsic defence mechanisms. The present study was performed to determine the protective effect of IPC on the rat renal ischemia-reperfusion injury (IRI) via miR-376c-3p/HIF-1α/VEGF axis. METHODS In vivo, these male Sprague-Dawley rats were treated by IRI and IPC. Meanwhile, these rats from different treatment groups were also injected subcutaneously with 2 nmol agomir-376c-3p and/or 10 nmol recombinant rat HIF-1α. At 72 h after reperfusion, serum samples were respectively collected for renal function. Besides, kidney tissues were harvested to observe renal morphology changes. Subsequently, the expression levels of CD31, HIF-1α and VEGF in the kidney tissues were measured using immunohistochemical staining, quantitative real-time PCR, as well as Western blotting analysis at the indicated time points after reperfusion. In vitro, HK-2 cells were used to detect the cell activity by CCK-8 and transfection of mir-376c-3p mimic in Hypoxia/Reoxygenation (H/R) group. RESULTS In vivo, the pathological changes were significantly relieved in the rats with IPC group, compared to the IRI group. Rats which were treated IPC significantly reduced the levels of blood urea nitrogen (BUN), serum creatinine (Scr) at 24 h after operation, compared to IRI group. After IPC treatment, the expression level of CD31 was obviously decreased, compared to IRI group. A total of differently expressed microRNAs were screened out by microRNA microarray assay in rat renal ischemia tissue, especially showing that miR-376c-3p was selected as the target miRNA. Compared to IRI group, the expression level of miR-376c-3p were obviously higher in IPC-treated group. Double-luciferase reporter assay demonstrated that miR-376c-3p directly targeted HIF-1α. In vitro, IPC significantly increased cell viability of HK-2, and promoted the angiogenesis via up-regulating miR-376c-3p/HIF-1α/VEGF axis. Furthermore, the expression level of HIF-1α was apparently decreased in HK-2 treated with H/R after miR-376c-3p mimic transfection respectively, as well as the increased expression level of VEGF. CONCLUSIONS Our study provided a novel insight for investigating the protective effect of IPC on renal IRI. Consequently, miR-376c-3p played an important role in renal IRI by promoting angiogenesis via targeting HIF-1α/VEGF pathway in male rats.
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Affiliation(s)
- Jianxin Xue
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Kai Zhu
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Pu Cao
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Chengcheng Long
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Youming Deng
- Department of Anesthesiology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Tieshi Liu
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Guoping Yin
- Department of Anesthesiology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, China
| | - Xiao Li
- Department of Urology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
| | - Zengjun Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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14
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Possible Preventative/Rehabilitative Role of Gliflozins in OSA and T2DM. A Systematic Literature Review-Based Hypothesis. Adv Ther 2021; 38:4195-4214. [PMID: 34273093 PMCID: PMC8342338 DOI: 10.1007/s12325-021-01791-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 05/13/2021] [Indexed: 02/07/2023]
Abstract
Obstructive sleep apnoea (OSA) is characterized by frequent apnoea episodes during sleep due to upper airway obstruction. The present review summarizes current knowledge on inter-relationships between OSA and type 2 diabetes mellitus (T2DM) and suggests the former as a possible target for sodium-glucose co-transporter-2 inhibitors (SGLT-2i). Based on pathophysiological mechanisms underlying OSA onset and renal SGLT-2 effects, we suggest that SGLT-2i indications might expand beyond current ones, including glucose, lipids, uric acid, blood pressure, and body weight control as well as chronic heart failure and kidney disease prevention.
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15
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Matthee C, Terre'Blanche G, Legoabe LJ, Janse van Rensburg HD. Exploration of chalcones and related heterocycle compounds as ligands of adenosine receptors: therapeutics development. Mol Divers 2021; 26:1779-1821. [PMID: 34176057 DOI: 10.1007/s11030-021-10257-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/15/2021] [Indexed: 12/20/2022]
Abstract
Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they are involved in an extensive list of physiological and pathological processes that scientists have only begun to decipher. Resultantly, AR agonists and antagonists have been the focus of multiple drug design and development programmes within the past few decades. Considered to be a privileged scaffold in medicinal chemistry, the chalcone framework has attracted a substantial amount of interest in this regard. Due to the potential liabilities associated with its structure, however, it has become necessary to explore other potentially promising compounds, such as heterocycles, which have successfully been obtained from chalcone precursors in the past. This review aims to summarise the emerging therapeutic importance of adenosine receptors and their ligands, especially in the central nervous system (CNS), while highlighting chalcone and heterocyclic derivatives as promising AR ligand lead compounds.
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Affiliation(s)
- Chrisna Matthee
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, North West, South Africa
| | - Gisella Terre'Blanche
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, North West, South Africa.,Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, North West, South Africa
| | - Lesetja J Legoabe
- Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, North West, South Africa
| | - Helena D Janse van Rensburg
- Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, North West, South Africa.
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16
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Liu P, Zhang Z, Li Y. Relevance of the Pyroptosis-Related Inflammasome Pathway in the Pathogenesis of Diabetic Kidney Disease. Front Immunol 2021; 12:603416. [PMID: 33692782 PMCID: PMC7937695 DOI: 10.3389/fimmu.2021.603416] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD) in many developed and developing countries. Pyroptosis is a recently discovered form of programmed cell death (PCD). With progress in research on DKD, researchers have become increasingly interested in elucidating the role of pyroptosis in DKD pathogenesis. This review focuses on the three pathways of pyroptosis generation: the canonical inflammasome, non-canonical inflammasome, and caspase-3-mediated inflammasome pathways. The molecular and pathophysiological mechanisms of the pyroptosis-related inflammasome pathway in the development of DKD are summarized. Activation of the diabetes-mediated pyroptosis-related inflammasomes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Toll-like receptor 4 (TLR4), caspase-1, interleukin (IL)-1β, and the IL-18 axis, plays an essential role in DKD lesions. By inhibiting activation of the TLR4 and NLRP3 inflammasomes, the production of caspase-1, IL-1β, and IL-18 is inhibited, thereby improving the pathological changes associated with DKD. Studies using high-glucose-induced cell models, high-fat diet/streptozotocin-induced DKD animal models, and human biopsies will help determine the spatial and temporal expression of DKD inflammatory components. Recent studies have confirmed the relationship between the pyroptosis-related inflammasome pathway and kidney disease. However, these studies are relatively superficial at present, and the mechanism needs further elucidation. Linking these findings with disease activity and prognosis would provide new ideas for DKD research.
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Affiliation(s)
- Pan Liu
- Department of Endocrinology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Zhengdong Zhang
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yao Li
- Department of Endocrinology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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17
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Boknik P, Eskandar J, Hofmann B, Zimmermann N, Neumann J, Gergs U. Role of Cardiac A 2A Receptors Under Normal and Pathophysiological Conditions. Front Pharmacol 2021; 11:627838. [PMID: 33574762 PMCID: PMC7871008 DOI: 10.3389/fphar.2020.627838] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/15/2020] [Indexed: 12/12/2022] Open
Abstract
This review presents an overview of cardiac A2A-adenosine receptors The localization of A2A-AR in the various cell types that encompass the heart and the role they play in force regulation in various mammalian species are depicted. The putative signal transduction systems of A2A-AR in cells in the living heart, as well as the known interactions of A2A-AR with membrane-bound receptors, will be addressed. The possible role that the receptors play in some relevant cardiac pathologies, such as persistent or transient ischemia, hypoxia, sepsis, hypertension, cardiac hypertrophy, and arrhythmias, will be reviewed. Moreover, the cardiac utility of A2A-AR as therapeutic targets for agonistic and antagonistic drugs will be discussed. Gaps in our knowledge about the cardiac function of A2A-AR and future research needs will be identified and formulated.
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Affiliation(s)
- P. Boknik
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Münster, Germany
| | - J. Eskandar
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Westfälische Wilhelms-Universität, Münster, Germany
| | - B. Hofmann
- Cardiac Surgery, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - N. Zimmermann
- Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
| | - J. Neumann
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - U. Gergs
- Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
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18
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Akomolafe SF, Olasehinde TA, Adewale OO, Ajayi OB. Curcumin Improves Biomolecules Associated with Renal Function and Attenuates Oxidative Injury and Histopathological Changes in Potassium-Induced Toxicity in Rats' Kidney. Biol Trace Elem Res 2021; 199:197-204. [PMID: 32277397 DOI: 10.1007/s12011-020-02113-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The protective effect of curcumin on potassium bromate (KBrO3)-induced renal damage was investigated in vivo. Treatment with KBrO3 (20 mg/kg bw) caused a significant increase in arginase and adenosine deaminase (ADA) activities in rats' kidney. However, oral administration of curcumin (20 mg/kg bw) caused a significant reduction in ADA and arginase activities in KBrO3 + CUR group. Furthermore, nitric oxide level was significantly low in KBrO3 group compared with the control. After treatment with curcumin in KBrO3 + CUR group, nitric oxide levels increased significantly (P < 0.05). Determination of some kidney biomarkers revealed elevated levels of creatinine, serum urea, and electrolytes (Na+ and Cl-) in KBrO3-treated rats. Curcumin effectively reduced the levels of these renal function parameters in KBrO3 + CUR groups and were not significantly different from the control. Antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities as well as glutathione (GSH) levels were significantly low with concomitant higher levels of malondialdehyde (MDA) after treatment with KBrO3. Curcumin caused a significant increase in SOD, CAT, and GPX activities including GSH levels with lower production of MDA in kidney homogenates of rats in KBrO3 + CUR. Curcumin ameliorated corpuscular degeneration in the kidney tissue and exhibited protection against tubular necrosis. These results revealed the protective effect of curcumin against KBrO3-induced renal toxicity by preventing degradation of ADA and arginine, improving antioxidant status and histopathological changes in rats' kidney.
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Affiliation(s)
- Seun F Akomolafe
- Department of Biochemistry, Faculty of Science, Ekiti State University, Ado Ekiti, Nigeria.
| | - Tosin A Olasehinde
- Department of Biochemistry, University of Fort Hare Alice, Eastern Cape, 5700, South Africa
- Department of Food Technology, Nutrition and Toxicology Division, Federal Institute of Industrial Research Oshodi, Lagos, Nigeria
| | - Omowumi O Adewale
- Department of Biochemistry, Faculty of Basic and Applied Sciences, Osun State University, Osogbo, Nigeria
| | - Olubunmi B Ajayi
- Department of Biochemistry, Faculty of Science, Ekiti State University, Ado Ekiti, Nigeria
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19
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Allard B, Allard D, Buisseret L, Stagg J. The adenosine pathway in immuno-oncology. Nat Rev Clin Oncol 2020; 17:611-629. [PMID: 32514148 DOI: 10.1038/s41571-020-0382-2] [Citation(s) in RCA: 334] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 12/14/2022]
Abstract
Cancer immunotherapy based on immune-checkpoint inhibition or adoptive cell therapy has revolutionized cancer care. Nevertheless, a large proportion of patients do not benefit from such treatments. Over the past decade, remarkable progress has been made in the development of 'next-generation' therapeutics in immuno-oncology, with inhibitors of extracellular adenosine (eADO) signalling constituting an expanding class of agents. Induced by tissue hypoxia, inflammation, tissue repair and specific oncogenic pathways, the adenosinergic axis is a broadly immunosuppressive pathway that regulates both innate and adaptive immune responses. Inhibition of eADO-generating enzymes and/or eADO receptors can promote antitumour immunity through multiple mechanisms, including enhancement of T cell and natural killer cell function, suppression of the pro-tumourigenic effects of myeloid cells and other immunoregulatory cells, and promotion of antigen presentation. With several clinical trials currently evaluating inhibitors of the eADO pathway in patients with cancer, we herein review the pathophysiological function of eADO with a focus on effects on antitumour immunity. We also discuss the treatment opportunities, potential limitations and biomarker-based strategies related to adenosine-targeted therapy in oncology.
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Affiliation(s)
- Bertrand Allard
- Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - David Allard
- Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Laurence Buisseret
- Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium
| | - John Stagg
- Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada.
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20
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Adenosine kinase inhibition attenuates ischemia reperfusion-induced acute kidney injury. Life Sci 2020; 256:117972. [PMID: 32544464 DOI: 10.1016/j.lfs.2020.117972] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/31/2020] [Accepted: 06/10/2020] [Indexed: 12/28/2022]
Abstract
Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl2) increased the level of oxidative stress, up-regulated the production of pro-inflammatory factor, and induced apoptosis, ADK inhibition could alleviate the above damaging effects. Moreover, the anti-apoptotic effect exerted by ADK inhibition was independent of inosine. In summary, our results support the idea that ADK inhibition has protective effects on IR-induced AKI. Adenosine kinase inhibition might provide a new target for AKI prevention and treatment.
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21
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Stryjak I, Warmuzińska N, Bogusiewicz J, Łuczykowski K, Bojko B. Monitoring of the influence of long-term oxidative stress and ischemia on the condition of kidneys using solid-phase microextraction chemical biopsy coupled with liquid chromatography-high-resolution mass spectrometry. J Sep Sci 2020; 43:1867-1878. [PMID: 32068348 DOI: 10.1002/jssc.202000032] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 02/11/2020] [Accepted: 02/11/2020] [Indexed: 12/28/2022]
Abstract
The limiting factor in conventional quality assessments of transplanted organs, namely the invasiveness of tissue sample collection, has prompted much research on the field of transplantology to focus on the development of alternative evaluation methods of organ quality. In the present project, we undertake the challenge to address the need for a new analytical solution for graft quality assessments by using a novel metabolomic diagnostic protocol based on low-invasive solid-phase microextraction. Solid-phase microextraction probes of ca. 0.2 mm coated with 4 mm long mixed-mode extraction phase were inserted into rabbit kidneys immediately following euthanasia and after 2, 4, 6, and 21 h of preservation. Liquid chromatography-mass spectrometry analysis of the extracts was performed with the use of a reversed phase column and a Q-Exactive Focus mass spectrometer operated in positive ionization mode. Statistical analysis of significantly changing compounds revealed metabolic profile changes in kidneys induced by ischemia and oxidative stress as a function of the duration of cold storage. The most pronounced alterations were reflected in levels of essential amino acids and purine nucleosides. Our findings demonstrate that the proposed approach may be successfully used to monitor changes in the metabolic profile of organs over time of preservation.
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Affiliation(s)
- Iga Stryjak
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Joanna Bogusiewicz
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
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22
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Perry HM, Görldt N, Sung SSJ, Huang L, Rudnicka KP, Encarnacion IM, Bajwa A, Tanaka S, Poudel N, Yao J, Rosin DL, Schrader J, Okusa MD. Perivascular CD73 + cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment. Am J Physiol Renal Physiol 2019; 317:F658-F669. [PMID: 31364375 PMCID: PMC6766625 DOI: 10.1152/ajprenal.00243.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023] Open
Abstract
Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5'-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73-/- kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.
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MESH Headings
- 5'-Nucleotidase/deficiency
- 5'-Nucleotidase/genetics
- 5'-Nucleotidase/metabolism
- Actins/metabolism
- Animals
- Cell Proliferation
- Cells, Cultured
- Cellular Microenvironment
- Collagen/metabolism
- Disease Models, Animal
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Fibrosis
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- GPI-Linked Proteins/deficiency
- GPI-Linked Proteins/genetics
- GPI-Linked Proteins/metabolism
- Inflammation Mediators/metabolism
- Kidney/immunology
- Kidney/metabolism
- Kidney/pathology
- Macrophages/metabolism
- Macrophages/pathology
- Male
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Nephritis, Interstitial/genetics
- Nephritis, Interstitial/immunology
- Nephritis, Interstitial/metabolism
- Nephritis, Interstitial/pathology
- Pericytes/metabolism
- Pericytes/pathology
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Reperfusion Injury/genetics
- Reperfusion Injury/immunology
- Reperfusion Injury/metabolism
- Reperfusion Injury/pathology
- Signal Transduction
- Wound Healing
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Affiliation(s)
- Heather M Perry
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Nicole Görldt
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
- Institute of Molecular Cardiology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Sun-Sang J Sung
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Liping Huang
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Kinga P Rudnicka
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Iain M Encarnacion
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Amandeep Bajwa
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Shinji Tanaka
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Nabin Poudel
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Junlan Yao
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
| | - Diane L Rosin
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia
| | - Jürgen Schrader
- Institute of Molecular Cardiology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Mark D Okusa
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia
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23
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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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24
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Zhou Q, Gong X, Kuang G, Jiang R, Xie T, Tie H, Chen X, Li K, Wan J, Wang B. Ferulic Acid Protected from Kidney Ischemia Reperfusion Injury in Mice: Possible Mechanism Through Increasing Adenosine Generation via HIF-1α. Inflammation 2019; 41:2068-2078. [PMID: 30143933 DOI: 10.1007/s10753-018-0850-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ferulic acid (FA), derived from fruits and vegetables, is well-known as a potent antioxidant of scavenging free radicals. However, the role and underlying mechanism of FA on kidney ischemia reperfusion (I/R) injury are limited. Here, we explored the effects of FA on kidney I/R injury. The kidney I/R injury models were carried out by clamping bilateral pedicles for 35 min followed by reperfusion for 24 h. Mice were orally pretreated with different doses of FA for three times 24 h before I/R. The renal function was assessed by serum creatine (Scr) and blood urea nitrogen (BUN). Kidney histology was examined by hematoxylin and eosin (HE) staining and terminal deoxynucleotidly transferased UTP nick-end labeling (TUNEL) assay. Proinflammatory cytokines, caspase-3 activity, adenosine generation, adenosine signaling molecules, and hypoxia inducible factor-1 alpha (HIF-1α) were also detected, respectively. The siHIF-1α adenovirus vectors were in vivo used to inhibit the expression of HIF-1α. The results showed that FA significantly attenuated kidney damage in renal I/R-operated mice as indicated by reducing levels of Scr and BUN, ameliorating renal pathological structural changes, and tubular cells apoptosis. Moreover, FA pretreatment inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment. Interestingly, the levels of HIF-α, CD39, and CD73 mRNA and protein as well as adenosine production were all significantly increased after FA pretreatment in the kidney of I/R-performed mice, and inhibiting HIF-α expression using siRNA abolished this protection of FA on I/R-induced acute kidney injury as evidenced by more severe renal damage and reduced adenosine production. Our findings indicated that FA protected against kidney I/R injury by reducing apoptosis, alleviating inflammation, increasing adenosine generation, and upregulating CD39 and CD73 expression, which might be mediated by HIF-1α.
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Affiliation(s)
- Qin Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, 400016, China
| | - Ge Kuang
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Tianjun Xie
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - HongTao Tie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - XiaHong Chen
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Ke Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - JingYuan Wan
- Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
| | - Bin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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25
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Dos Santos IF, Sheriff S, Amlal S, Ahmed RPH, Thakar CV, Amlal H. Adenine acts in the kidney as a signaling factor and causes salt- and water-losing nephropathy: early mechanism of adenine-induced renal injury. Am J Physiol Renal Physiol 2019; 316:F743-F757. [PMID: 30623725 DOI: 10.1152/ajprenal.00142.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Chronic adenine feeding is extensively used to develop animal models of chronic renal failure with metabolic features resembling those observed in humans. However, the mechanism by which adenine induces renal failure is poorly understood. In this study, we examined the early effects of adenine on water metabolism and salt balance in rats placed in metabolic cages and fed control or adenine-containing diets for 7 days. Molecular and functional studies demonstrated that adenine-fed rats exhibited a significant reduction in food intake, polyuria, polydipsia, decreased urine osmolality, and increased salt wasting. These effects are independent of changes in food intake and result from a coordinated downregulation of water channel aquaporin-2 (AQP2) and salt transporter (Na+-K+-Cl- cotransporter 2; NKCC2) in the collecting duct and medullary thick ascending limb, respectively. As a result, adenine-fed rats exhibited massive volume depletion, as indicated by a significant body weight loss, increased blood urea nitrogen, and increased hematocrit and hemoglobin levels, all of which were significantly corrected with NaCl replacement. Adenine-induced urinary concentrating defect was not corrected by exogenous arginine vasopressin (AVP), and it correlated with reduced cAMP production in vivo and in vitro. In conclusion, adenine acts on renal tubules as a signaling molecule and causes nephrogenic diabetes insipidus with salt wasting, at least, by directly interfering with AVP V2 receptor signaling with subsequent downregulation of NKCC2 and AQP2 in the kidney. The combination of renal fluid loss and decreased food intake with subsequent massive volume depletion likely plays an important role in the development of early prerenal failure that progresses to chronic kidney disease in long-term adenine feeding.
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Affiliation(s)
- Ingrid F Dos Santos
- Department of Internal Medicine, Division of Nephrology and Kidney C.A.R.E, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Sulaiman Sheriff
- Department of Surgery, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Sihame Amlal
- Department of Internal Medicine, Division of Nephrology and Kidney C.A.R.E, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Rafeeq P H Ahmed
- Department of Pathology, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Charuhas V Thakar
- Department of Internal Medicine, Division of Nephrology and Kidney C.A.R.E, College of Medicine, University of Cincinnati , Cincinnati, Ohio
| | - Hassane Amlal
- Department of Internal Medicine, Division of Nephrology and Kidney C.A.R.E, College of Medicine, University of Cincinnati , Cincinnati, Ohio
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26
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Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K. Pharmacology of Adenosine Receptors: The State of the Art. Physiol Rev 2018; 98:1591-1625. [PMID: 29848236 DOI: 10.1152/physrev.00049.2017] [Citation(s) in RCA: 518] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine from cellular metabolism, and the widespread distribution of its receptor subtypes in almost all organs and tissues, this nucleoside induces a multitude of physiopathological effects, regulating central nervous, cardiovascular, peripheral, and immune systems. It is becoming clear that the expression patterns of adenosine receptors vary among cell types, lending weight to the idea that they may be both markers of pathologies and useful targets for novel drugs. This review offers an overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases. Finally, we highlight the latest findings on molecules capable of targeting adenosine receptors and report which stage of drug development they have reached.
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Affiliation(s)
- Pier Andrea Borea
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Stefania Gessi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Stefania Merighi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Fabrizio Vincenzi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Katia Varani
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
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27
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Yu J, Kim G, Jarhad DB, Lee HW, Lee J, Park CW, Ha H, Jeong LS. Correlation study between A 3 adenosine receptor binding affinity and anti-renal interstitial fibrosis activity of truncated adenosine derivatives. Arch Pharm Res 2018; 42:773-779. [PMID: 30264323 DOI: 10.1007/s12272-018-1079-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/07/2018] [Indexed: 11/28/2022]
Abstract
Truncated 4'-thionucleosides 1-4 and 4'-oxonucleosides 5-8 as potent and selective A3AR antagonists were synthesized from D-mannose and D-erythronic acid γ-lactone, respectively. These nucleosides were evaluated for their anti-fibrotic renoprotective activity in TGF-β1-treated murine proximal tubular (mProx) cells. Their antagonistic activities for A3AR were proportional to their inhibitory activities against TGF-β1-induced collagen I upregulation in mProx cells. This result suggests that the binding affinity of A3AR antagonists is closely correlated with their anti-fibrotic activity. Thus, A3AR antagonists might be novel therapeutic candidates for treating chronic kidney disease.
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Affiliation(s)
- Jinha Yu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
| | - Gyudong Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
| | - Dnyandev B Jarhad
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
| | | | - Jiyoun Lee
- Future Medicine Co., Ltd., Seoul, 06665, Korea
| | | | - Hunjoo Ha
- College of Pharmacy, Ewha Womans University, Seoul, 03761, Korea
| | - Lak Shin Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea.
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28
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Kishore BK, Robson SC, Dwyer KM. CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal 2018; 14:109-120. [PMID: 29332180 PMCID: PMC5940625 DOI: 10.1007/s11302-017-9596-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 11/28/2017] [Indexed: 12/12/2022] Open
Abstract
Extracellular ATP interacts with purinergic type 2 (P2) receptors and elicits many crucial biological functions. Extracellular ATP is sequentially hydrolyzed to ADP and AMP by the actions of defined nucleotidases, such as CD39, and AMP is converted to adenosine, largely by CD73, an ecto-5'-nucleotidase. Extracellular adenosine interacts with P1 receptors and often opposes the effects of P2 receptor activation. The balance between extracellular ATP and adenosine in the blood and extracellular fluid is regulated chiefly by the activities of CD39 and CD73, which constitute the CD39-adenosinergic axis. In recent years, several studies have shown this axis to play critical roles in transport of water/sodium, tubuloglomerular feedback, renin secretion, ischemia reperfusion injury, renal fibrosis, hypertension, diabetic nephropathy, transplantation, inflammation, and macrophage transformation. Important developments include global and targeted gene knockout and/or transgenic mouse models of CD39 or CD73, biological or small molecule inhibitors, and soluble engineered ectonucleotidases to directly impact the CD39-adenosinergic axis. This review presents a comprehensive picture of the multiple roles of CD39-adenosinergic axis in renal physiology, pathophysiology, and therapeutics. Scientific advances and greater understanding of the role of this axis in the kidney, in both health and illness, will direct development of innovative therapies for renal diseases.
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Affiliation(s)
- Bellamkonda K. Kishore
- Departments of Internal Medicine and Nutrition & Integrative Physiology, and Center on Aging, University of Utah Health, Salt Lake City, UT USA
- Nephrology Research, VA Salt Lake City Health Care System, 500 Foothill Drive (151M), Salt Lake City, UT 84148 USA
| | - Simon C. Robson
- Division of Gastroenterology/Hepatology and Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 USA
| | - Karen M. Dwyer
- School of Medicine, Faculty of Health, Deakin University, Geelong, VIC 3220 Australia
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29
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Dorotea D, Cho A, Lee G, Kwon G, Lee J, Sahu PK, Jeong LS, Cha DR, Ha H. Orally active, species-independent novel A 3 adenosine receptor antagonist protects against kidney injury in db/db mice. Exp Mol Med 2018; 50:1-14. [PMID: 29674631 PMCID: PMC5938017 DOI: 10.1038/s12276-018-0053-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 11/25/2017] [Accepted: 12/18/2017] [Indexed: 11/22/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A1AR, A2aAR, A2bAR, and A3AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A3AR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A3AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A3AR antagonist, may become a novel therapeutic agent against DKD. A therapeutic treatment targeting a protein involved in the progression of diabetic kidney disease (DKD) shows promise in mouse trials. Between 30 and 40 per cent of diabetic patients suffer from DKD, a common cause to fatal end-stage kidney disease. Protein receptors, commonly expressed on cell surfaces throughout the body, play both positive and negative roles in diseases. The A3 adenosine receptor (A3AR) is highly expressed in diabetic kidney tissue, and is linked to disease progression. Hunjoo Ha at Ewha Womans University in Seoul, Republic of Korea, and co-workers demonstrated the positive effect of a novel drug in targeting A3AR in mice with DKD. A 12-week treatment of the drug prevented kidney injury, lowered oxidative stress and inflammation, and improved kidney function. It may prove an invaluable drug, particularly in combination with an existing DKD drug.
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Affiliation(s)
- Debra Dorotea
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Ahreum Cho
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Gayoung Lee
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Guideock Kwon
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Junghwa Lee
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Pramod K Sahu
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.,Future Medicine Co, Seoul, Korea
| | - Lak Shin Jeong
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Dae Ryong Cha
- Department of Nephrology, Korea University Ansan Hospital, Ansan, Korea
| | - Hunjoo Ha
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
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30
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Dugbartey GJ, Hardenberg MC, Kok WF, Boerema AS, Carey HV, Staples JF, Henning RH, Bouma HR. Renal Mitochondrial Response to Low Temperature in Non-Hibernating and Hibernating Species. Antioxid Redox Signal 2017; 27:599-617. [PMID: 28322600 DOI: 10.1089/ars.2016.6705] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
SIGNIFICANCE Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is believed to be a key event triggering loss of cellular homeostasis, and potentially cell death. Subsequent rewarming generates large amounts of reactive oxygen species that aggravate organ injury. Recent Advances: Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature ("torpor"), interspersed by brief periods of rewarming ("arousal") without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress, and protect against cell death. These adaptations consist of active suppression of mitochondrial function and upregulation of anti-oxidant enzymes and anti-apoptotic pathways. CRITICAL ISSUES Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit IRI in patients. FUTURE DIRECTIONS Although the precise signaling routes involved in natural hibernation are not yet fully understood, torpor-like hypothermic states with increased resistance to ischemia/reperfusion can be induced pharmacologically by 5'-adenosine monophosphate (5'-AMP), adenosine, and hydrogen sulfide (H2S) in non-hibernators. In this review, we compare the molecular effects of hypothermia in non-hibernators with natural and pharmacologically induced torpor, to delineate how safe and reversible metabolic suppression may provide resistance to renal IRI. Antioxid. Redox Signal. 27, 599-617.
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Affiliation(s)
- George J Dugbartey
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .,2 Division of Cardiology, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Maarten C Hardenberg
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Wendelinde F Kok
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Ate S Boerema
- 3 Groningen Institute for Evolutionary Life Sciences, University of Groningen , Groningen, the Netherlands .,4 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Hannah V Carey
- 5 Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin , Madison, Wisconsin
| | - James F Staples
- 6 Department of Biology, University of Western Ontario , London, Canada
| | - Robert H Henning
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
| | - Hjalmar R Bouma
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .,7 Department of Internal Medicine, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands
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Affiliation(s)
- S. Reuter
- Klinik für Innere Medizin III; AG Experimentelle Nephrologie; Universitätsklinikum Jena; Jena Germany
| | - R. Mrowka
- Klinik für Innere Medizin III; AG Experimentelle Nephrologie; Universitätsklinikum Jena; Jena Germany
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Peleli M, Carlstrom M. Adenosine signaling in diabetes mellitus and associated cardiovascular and renal complications. Mol Aspects Med 2017; 55:62-74. [DOI: 10.1016/j.mam.2016.12.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/18/2016] [Accepted: 12/21/2016] [Indexed: 12/21/2022]
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Affiliation(s)
- P. B. Persson
- Institut für vegetative Physiologie; Charité-Universitätsmedizin; Berlin Germany
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34
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Biasutto L, Azzolini M, Szabò I, Zoratti M. The mitochondrial permeability transition pore in AD 2016: An update. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1863:2515-30. [PMID: 26902508 DOI: 10.1016/j.bbamcr.2016.02.012] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/04/2016] [Accepted: 02/05/2016] [Indexed: 12/13/2022]
Abstract
Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
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Affiliation(s)
- Lucia Biasutto
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy
| | - Michele Azzolini
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy
| | - Ildikò Szabò
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biology, Viale G. Colombo 3, 35121 Padova, Italy
| | - Mario Zoratti
- CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy; University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
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Yang T, Zollbrecht C, Winerdal ME, Zhuge Z, Zhang XM, Terrando N, Checa A, Sällström J, Wheelock CE, Winqvist O, Harris RA, Larsson E, Persson AEG, Fredholm BB, Carlström M. Genetic Abrogation of Adenosine A3 Receptor Prevents Uninephrectomy and High Salt-Induced Hypertension. J Am Heart Assoc 2016; 5:JAHA.116.003868. [PMID: 27431647 PMCID: PMC5015411 DOI: 10.1161/jaha.116.003868] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Early‐life reduction in nephron number (uninephrectomy [UNX]) and chronic high salt (HS) intake increase the risk of hypertension and chronic kidney disease. Adenosine signaling via its different receptors has been implicated in modulating renal, cardiovascular, and metabolic functions as well as inflammatory processes; however, the specific role of the A3 receptor in cardiovascular diseases is not clear. In this study, gene‐modified mice were used to investigate the hypothesis that lack of A3 signaling prevents the development of hypertension and attenuates renal and cardiovascular injuries following UNX in combination with HS (UNX‐HS) in mice. Methods and Results Wild‐type (A3+/+) mice subjected to UNX‐HS developed hypertension compared with controls (mean arterial pressure 106±3 versus 82±3 mm Hg; P<0.05) and displayed an impaired metabolic phenotype (eg, increased adiposity, reduced glucose tolerance, hyperinsulinemia). These changes were associated with both cardiac hypertrophy and fibrosis together with renal injuries and proteinuria. All of these pathological hallmarks were significantly attenuated in the A3−/− mice. Mechanistically, absence of A3 receptors protected from UNX‐HS–associated increase in renal NADPH oxidase activity and Nox2 expression. In addition, circulating cytokines including interleukins 1β, 6, 12, and 10 were increased in A3+/+ following UNX‐HS, but these cytokines were already elevated in naïve A3−/− mice and did not change following UNX‐HS. Conclusions Reduction in nephron number combined with chronic HS intake is associated with oxidative stress, chronic inflammation, and development of hypertension in mice. Absence of adenosine A3 receptor signaling was strongly protective in this novel mouse model of renal and cardiovascular disease.
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Affiliation(s)
- Ting Yang
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Christa Zollbrecht
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Malin E Winerdal
- Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Zhengbing Zhuge
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Xing-Mei Zhang
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Niccolo Terrando
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Antonio Checa
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Johan Sällström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Craig E Wheelock
- Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ola Winqvist
- Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Robert A Harris
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Erik Larsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - A Erik G Persson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Bertil B Fredholm
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Li K, Gong X, Kuang G, Jiang R, Wan J, Wang B. Sesamin protects against renal ischemia reperfusion injury by promoting CD39-adenosine-A2AR signal pathway in mice. Am J Transl Res 2016; 8:2245-2254. [PMID: 27347331 PMCID: PMC4891436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/03/2016] [Indexed: 06/06/2023]
Abstract
Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. Here, we examine whether sesamin attenuates renal IRI in an animal model and explore the underlying mechanisms. Male mice were subjected to right renal ischemia for 30 min followed by reperfusion for 24 h with sesamin (100 mg/kg) during which the left kidney was removed. Renal damage and function were assessed subsequently. The results showed that sesamin reduced kidney ischemia reperfusion injury, as assessed by decreased serum creatinine (Scr) and Blood urea nitrogen (BUN), alleviated tubular damage and apoptosis. In addition, sesamin inhibited neutrophils infiltration and pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in IR-preformed kidney. Notably, sesamin promoted the expression of CD39, A2A adenosine receptor (A2AAR), and A2BAR mRNA and protein as well as adenosine production. Furthermore, CD39 inhibitor or A2AR antagonist abolished partly the protection of sesamin in kidney IRI. In conclusion, sesamin could effectively protect kidney from IRI by inhibiting inflammatory responses, which might be associated with promoting the adenosine-CD39-A2AR signaling pathway.
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Affiliation(s)
- Ke Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016, China
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical UniversityChongqing 400016, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical UniversityChongqing 400016, China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical UniversityChongqing 400016, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical UniversityChongqing 400016, China
| | - Bin Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016, China
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016, China
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Squarcialupi L, Catarzi D, Varano F, Betti M, Falsini M, Vincenzi F, Ravani A, Ciancetta A, Varani K, Moro S, Colotta V. Structural refinement of pyrazolo[4,3-d]pyrimidine derivatives to obtain highly potent and selective antagonists for the human A3 adenosine receptor. Eur J Med Chem 2015; 108:117-133. [PMID: 26638043 DOI: 10.1016/j.ejmech.2015.11.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/06/2015] [Accepted: 11/07/2015] [Indexed: 02/09/2023]
Abstract
In previous research, we identified some 7-oxo- and 7-acylamino-substituted pyrazolo[4,3-d]pyrimidine derivatives as potent and selective human (h) A3 adenosine receptor (AR) antagonists. Herein we report on the structural refinement of this class of antagonists aimed at achieving improved receptor-ligand recognition. Hence, substituents with different steric bulk, flexibility and lipophilicity (Me, Ar, heteroaryl, CH2Ph) were introduced at the 5- and 2-positions of the bicyclic scaffold of both the 7-oxo and 7-amino derivatives, and acyl residues were appended on the 7-amino group of the latter. All the 2-phenylpyrazolo[4,3-d]pyrimidin-7-amines and 7-acylamines bearing a 4-methoxyphenyl- or a 2-thienyl group at the 5-position showed high hA3 affinity and selectivity. In particular, the 2-phenyl-5-(2-thienyl)-pyrazolo[4,3-d]pyrimidin-7-(4-methoxybenzoyl)amine 25 (Ki = 0.027 nM) is one of the most potent and selective hA3 antagonists reported so far. By using an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinities were critically described.
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Affiliation(s)
- Lucia Squarcialupi
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy
| | - Daniela Catarzi
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy
| | - Flavia Varano
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy
| | - Marco Betti
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy
| | - Matteo Falsini
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy
| | - Fabrizio Vincenzi
- Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy
| | - Annalisa Ravani
- Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy
| | - Antonella Ciancetta
- Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, via Marzolo 5, 35131, Padova, Italy
| | - Katia Varani
- Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy
| | - Stefano Moro
- Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, via Marzolo 5, 35131, Padova, Italy.
| | - Vittoria Colotta
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e salute del Bambino, sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.
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Affiliation(s)
- S. Reuter
- Klinik für Innere Medizin III; AG Experimentelle Nephrologie; Universitätsklinikum Jena; Jena Germany
| | - R. Mrowka
- Klinik für Innere Medizin III; AG Experimentelle Nephrologie; Universitätsklinikum Jena; Jena Germany
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Recent knowledge on the pathophysiology of septic acute kidney injury: A narrative review. J Crit Care 2015; 31:82-9. [PMID: 26475099 DOI: 10.1016/j.jcrc.2015.09.017] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 09/13/2015] [Accepted: 09/13/2015] [Indexed: 01/03/2023]
Abstract
Sepsis is the commonest cause of acute kidney injury in critically ill patients. Its pathophysiology is complex and not well understood. Until recently, it was believed that kidney hypoperfusion is the major contributor of septic acute kidney injury. However, recent publications have improved our understanding on this topic. We now know that its mechanisms included the following: (1) renal macrocirculatory and microcirculatory disturbance, (2) surge of inflammatory markers and oxidative stress, (3) coagulation cascade activation, and (4) bioenergetics adaptive response with controlled cell-cycle arrest aiming to prevent cell death. Uncovering these complicated mechanisms may facilitate the development of more appropriate therapeutic measures in the future.
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Persson AEG, Carlström M. Renal purinergic signalling in health and disease. Acta Physiol (Oxf) 2015; 213:805-7. [PMID: 25613023 DOI: 10.1111/apha.12459] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- A. E. G. Persson
- Department of Medical Cellbiology; Uppsala University; Uppsala Sweden
| | - M. Carlström
- Department of Physiology and Pharmacology; Karolinska Institutet; Stockholm Sweden
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