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Wang Y, Wu Y, Ren J, Wang Y, Perwaiz I, Su H, Li J, Qu P. Pharmacological inhibition of the NLRP3 inflammasome attenuates kidney apoptosis, fibrosis, and injury in Dahl salt-sensitive rats. Clin Exp Nephrol 2025; 29:113-122. [PMID: 39576390 PMCID: PMC11807026 DOI: 10.1007/s10157-024-02567-7] [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: 02/22/2024] [Accepted: 09/12/2024] [Indexed: 02/09/2025]
Abstract
BACKGROUND Salt-sensitive hypertension (SSH) is the most severe form of hypertension, and the presence of NLRP3 inflammasome plays a crucial role in its pathogenesis. Although MCC950 has shown therapeutic potential for hypertension and kidney injury, its mechanism of action remains unclear. METHODS Dahl salt-sensitive (SS) rats and their salt-tolerant aptamer control SS-13BN (BN) rats were randomly assigned to four groups: SS rats intraperitoneally administered physiological saline (SS + vehicle) or MCC950 (SS + MCC950), and BN rats intraperitoneally administered physiological saline (BN + vehicle) or MCC950 (BN + MCC950). All rats were given 2% saline for drinking and received intraperitoneal injections of physiological saline or MCC950 (5 mg/kg) every other day. Biomarkers such as serum creatinine, urinary protein, sodium retention, NLRP3 inflammasome, inflammation, apoptosis, fibrosis, sodium channels and histopathological changes in kidney injury were evaluated in blood, urine, and kidney tissues. RESULTS Compared with the SS + vehicle group, the SS + MCC950 group showed significantly lower blood pressure levels. Additionally, inhibition of NLRP3 inflammasome activation was observed along with reduced inflammation, apoptosis, fibrosis, and sodium retention in the kidneys. CONCLUSIONS The findings suggest that pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure in SS rats and alleviates related kidney injury by suppressing inflammation, apoptosis, fibrosis, and sodium retention.
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Affiliation(s)
- Yue Wang
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Yuhang Wu
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Jiayu Ren
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Ying Wang
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Imran Perwaiz
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Hongtong Su
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Jing Li
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China
| | - Peng Qu
- Institute of Heart and Vessel Diseases, The Second Hospital Affiliated of Dalian Medical University, Dalian, 116000, China.
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Lu X, Ma K, Ren J, Peng H, Wang J, Wang X, Nasser MI, Liu C. The immune regulatory role of lymphangiogenesis in kidney disease. J Transl Med 2024; 22:1053. [PMID: 39578812 PMCID: PMC11583545 DOI: 10.1186/s12967-024-05859-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/04/2024] [Indexed: 11/24/2024] Open
Abstract
The renal lymphatic system is critical for maintaining kidney homeostasis and regulating the immune response inside the kidney. In various kidney pathological situations, the renal lymphatic network experiences lymphangiogenesis, which is defined as the creation of new lymphatic vessels. Kidney lymphangiogenesis controls immunological response inside the kidney by controlling lymphatic flow, immune cell trafficking, and immune cell regulation. Ongoing study reveals lymphangiogenesis's different architecture and functions in numerous tissues and organs. New research suggests that lymphangiogenesis in kidney disorders may regulate the renal immune response in various ways. The flexibility of lymphatic endothelial cells (LECs) improves the kidney's immunological regulatory function of lymphangiogenesis. Furthermore, current research has shown disparate findings regarding its impact on distinct renal diseases, resulting in contradictory outcomes even within the same kidney condition. The fundamental causes of the various effects of lymphangiogenesis on renal disorders remain unknown. In this thorough review, we explore the dual impacts of renal lymphangiogenesis on several kidney pathologies, with a particular emphasis on existing empirical data and new developments in understanding its immunological regulatory function in kidney disease. An improved understanding of the immunological regulatory function of lymphangiogenesis in kidney diseases might help design novel medicines targeting lymphatics to treat kidney pathologies.
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Affiliation(s)
- Xiangheng Lu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Junyi Ren
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Haoyu Peng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jia Wang
- General Practice Center, Sichuan Academy of Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, 610072, China
| | - Xiaoxiao Wang
- Department of Organ Transplantation, School of Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
| | - Moussa Ide Nasser
- Department of Cardiac Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, Southern Medical University, Guangzhou, 510100, Guangdong, China.
| | - Chi Liu
- Department of Nephrology and Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Centre for Kidney Diseases, Chengdu, China.
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Smith HL, Goodlett BL, Navaneethabalakrishnan S, Mitchell BM. Elevated Salt or Angiotensin II Levels Induce CD38+ Innate Immune Cells in the Presence of Granulocyte-Macrophage Colony Stimulating Factor. Cells 2024; 13:1302. [PMID: 39120331 PMCID: PMC11311366 DOI: 10.3390/cells13151302] [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: 07/08/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024] Open
Abstract
Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] innate immune cells, such as macrophages and dendritic cells (DCs), play distinct roles in modulating renal function and blood pressure. It is unknown how these cells become CD38+ or which subtypes are pro-hypertensive. When bone marrow-derived monocytes (BMDMs) were grown in granulocyte-macrophage colony stimulating factor (GM-CSF) and treated with salt or A2, CD38+ macrophages and CD38+ DCs increased. The adoptive transfer of GM-CSF-primed BMDMs into mice with either SSHTN or A2HTN increased renal CD38+ macrophages and CD38+ DCs. Flow cytometry revealed increased renal M1 macrophages and type-2 conventional DCs (cDC2s), along with their CD38+ counterparts, in mice with either SSHTN or A2HTN. These results were replicable in vitro. Either salt or A2 treatment of GM-CSF-primed BMDMs significantly increased bone marrow-derived (BMD)-M1 macrophages, CD38+ BMD-M1 macrophages, BMD-cDC2s, and CD38+ BMD-cDC2s. Overall, these data suggest that GM-CSF is necessary for the salt or A2 induction of CD38+ innate immune cells, and that CD38 distinguishes pro-hypertensive immune cells. Further investigation of CD38+ M1 macrophages and CD38+ cDC2s could provide new therapeutic targets for both SSHTN and A2HTN.
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Affiliation(s)
| | | | | | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M School of Medicine, Bryan, TX 77807, USA; (H.L.S.)
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Xiao T, Wu A, Wang X, Guo Z, Huang F, Cheng X, Shen X, Tao L. Anti-hypertensive and composition as well as pharmacokinetics and tissues distribution of active ingredients from Alpinia zerumbet. Fitoterapia 2024; 172:105753. [PMID: 37992780 DOI: 10.1016/j.fitote.2023.105753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/11/2023] [Accepted: 11/13/2023] [Indexed: 11/24/2023]
Abstract
Alpinia zerumbet is a food flavor additive and a traditional medicine herb around the world. Several studies have reported that A. zerumbet has excellent effects on a variety of cardiovascular diseases, but its potential hypertensive applications, and pharmacokinetic features of main active substances have not been fully investigated. The mechanism of anti-hypertension with ethyl acetate extracts of A. zerumbet fruits (AZEAE) was evaluated by L-NNA-induced hypertensive rats and L-NAME-injured human umbilical vein endothelial cells (HUVECs). Blood pressure, echocardiographic cardiac index and H&E staining were used to preliminary evaluate the antihypertensive effect of AZEAE, the levels of TNF-α, IL-6, and IL-1β were evaluated by ELISA, and the proteins expression of IL-1β, IL-18, AGTR1, VCAM, iNOS, EDN1 and eNOS were also evaluated. In addition, isolation, identification, and activity screening of bioactive compounds were carried ou. Next, pharmacokinetics and tissues distribution of dihydro-5,6-dehydrokavain (DDK) in vivo were measured, and preliminary absorption mechanism was conducted with Caco-2 cell monolayers. AZEAE remarkably enhanced the state of hypertensive rats. Twelve compounds were isolated and identified, and five compounds were isolated from this plant for the first time. The isolated compounds also exhibited good resistance against injury of HUVECs. Moreover, pharmacokinetics and Caco-2 cell monolayers demonstrated AZEAE had better absorption capacity than DDK, and DDK exhibited differences in tissues distribution and gender difference. This study was the first to assess the potential hypertensive applications of A. zerumbet in vivo and vitro, and the first direct and concise study of the in vivo behavior of DDK and AZEAE.
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Affiliation(s)
- Ting Xiao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China.
| | - Ai Wu
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China
| | - Xiaowei Wang
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China
| | - Zhenghong Guo
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou, China
| | - Feilong Huang
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China
| | - Xingyan Cheng
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China
| | - Xiangchun Shen
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China.
| | - Ling Tao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, NO. 6 Ankang avenue, Guian New District, 561113, Guizhou, China.
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Wu G, Liu F, Cui Q, Zhang T, Bao J, Hao J. Quercetin Prevents Hypertension in Dahl Salt-sensitive Rats F ed a High-salt Diet Through Balancing Endothelial Nitric Oxide Synthase and Sirtuin 1. Comb Chem High Throughput Screen 2024; 27:2446-2453. [PMID: 38415447 DOI: 10.2174/0113862073284196240214082904] [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: 11/06/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND A high-salt diet is a leading dietary risk factor for elevated blood pressure and cardiovascular disease. Quercetin reportedly exhibits cardioprotective and antihypertensive therapeutic effects. OBJECTIVES The objective of this study is to examine the effect of quercetin on high-salt dietinduced elevated blood pressure in Dahl salt-sensitive (SS) rats and determine the underlying molecular mechanism. MATERIALS AND METHODS Rats of the Dahl SS and control SS-13 BN strains were separated into five groups, SS-13 BN rats fed a low-salt diet (BL group), SS-13 BN rats fed a high-salt diet (BH group), Dahl SS rats fed a low-salt diet (SL group), Dahl SS rats fed a high-salt diet (SH group), and SH rats treated with quercetin (SHQ group). Blood pressure was checked three weeks into the course of treatment, and biochemical markers in the urine and serum were examined. Additionally, western blot was done to evaluate the sirtuin 1 (SIRT1) and endothelial nitric oxide synthase (eNOS) expression levels. Immunohistochemical analysis was performed to verify SIRT1 levels. RESULTS We demonstrated that a high-salt diet elevated blood pressure in both SS-13 BN and Dahl SS rats, and quercetin supplementation alleviated the altered blood pressure. Compared with the SH group, quercetin significantly elevated the protein expression of SIRT1 and eNOS. Immunohistochemistry results further confirmed that quercetin could improve the protein expression of SIRT1. CONCLUSION Quercetin reduced blood pressure by enhancing the expression of SIRT1 and eNOS in Dahl SS rats fed a high-salt diet.
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Affiliation(s)
- Guanji Wu
- Department of Cardiology, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
- Department of Cardiology, Xi'an Central Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Fuqiang Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Qing Cui
- Department of Cardiology, Xi'an Central Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Tao Zhang
- Department of Cardiology, Xi'an Central Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Jianjun Bao
- Department of Cardiology, Xi'an Central Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Junjun Hao
- Department of Cardiovascular Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, China
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6
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Shimoura CG, Stubbs CY, Chaudhari S, Dinh VQ, Mathis KW. Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus. Auton Neurosci 2023; 250:103129. [PMID: 37950930 PMCID: PMC11259125 DOI: 10.1016/j.autneu.2023.103129] [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: 08/31/2023] [Revised: 10/25/2023] [Accepted: 10/28/2023] [Indexed: 11/13/2023]
Abstract
Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age. After two weeks of recovery and viral transfection, the DREADD agonist clozapine-N-oxide (CNO; 3 mg/kg) was injected subcutaneously for an additional 14 days. At 35 weeks, mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to NZW mice, but selective activation of DMV neurons did not significantly alter MAP in either group. SLE mice had higher indices of renal injury including albumin excretion rate (μg/day), glomerulosclerosis index, interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to NZW mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not NZW mice. Together, these data indicate that selective activation of neurons within the DMV by DREADD protects the kidney suggesting an important role of vagus-mediated pathways in the progression of renal injury in SLE.
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Affiliation(s)
- Caroline Gusson Shimoura
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States of America
| | - Cassandra Y Stubbs
- Department of Internal Medicine, Division of Rheumatic Diseases, University of Texas Southwestern, Dallas, TX, United States of America
| | - Sarika Chaudhari
- Department of Internal Medicine, Division of Rheumatic Diseases, University of Texas Southwestern, Dallas, TX, United States of America
| | - Viet Q Dinh
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States of America
| | - Keisa W Mathis
- Department of Internal Medicine, Division of Rheumatic Diseases, University of Texas Southwestern, Dallas, TX, United States of America.
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Shin J, Lee CH. The roles of sodium and volume overload on hypertension in chronic kidney disease. Kidney Res Clin Pract 2021; 40:542-554. [PMID: 34922428 PMCID: PMC8685361 DOI: 10.23876/j.krcp.21.800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 10/18/2021] [Indexed: 11/24/2022] Open
Abstract
Chronic kidney disease (CKD) is associated with increased risk of cardiovascular (CV) events, and the disease burden is rising rapidly. An important contributor to CV events and CKD progression is high blood pressure (BP). The main mechanisms of hypertension in early and advanced CKD are renin-angiotensin system activation and volume overload, respectively. Sodium retention is well known as a factor for high BP in CKD. However, a BP increase in response to total body sodium or volume overload can be limited by neurohormonal modulation. Recent clinical trial data favoring intensive BP lowering in CKD imply that the balance between volume and neurohormonal control could be revisited with respect to the safety and efficacy of strict volume control when using antihypertensive medications. In hemodialysis patients, the role of more liberal use of antihypertensive medications with the concept of functional dry weight for intensive BP control must be studied.
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Affiliation(s)
- Jinho Shin
- Division of Cardiology, Department of Internal Medicine, Hanyang University Medical Center, Seoul, Republic of Korea
| | - Chang Hwa Lee
- Division of Nephrology, Department of Internal Medicine, Hanyang University Medical Center, Seoul, Republic of Korea
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The Pathophysiological Role of Heat Shock Response in Autoimmunity: A Literature Review. Cells 2021; 10:cells10102626. [PMID: 34685607 PMCID: PMC8533860 DOI: 10.3390/cells10102626] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings.
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Albino AH, Zambom FFF, Foresto-Neto O, Oliveira KC, Ávila VF, Arias SCA, Seguro AC, Malheiros DMAC, Camara NOS, Fujihara CK, Zatz R. Renal Inflammation and Innate Immune Activation Underlie the Transition From Gentamicin-Induced Acute Kidney Injury to Renal Fibrosis. Front Physiol 2021; 12:606392. [PMID: 34305624 PMCID: PMC8293269 DOI: 10.3389/fphys.2021.606392] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 06/11/2021] [Indexed: 01/15/2023] Open
Abstract
Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disease (CKD). The mechanisms underlying this transition are unclear and may involve sustained activation of renal innate immunity, with resulting renal inflammation and fibrosis. We investigated whether the NF-κB system and/or the NLRP3 inflammasome pathway remain activated after the resolution of AKI induced by gentamicin (GT) treatment, thus favoring the development of CKD. Male Munich-Wistar rats received daily subcutaneous injections of GT, 80 mg/kg, for 9 days. Control rats received vehicle only (NC). Rats were studied at 1, 30, and 180 days after GT treatment was ceased. On Day 1, glomerular ischemia (ISCH), tubular necrosis, albuminuria, creatinine retention, and tubular dysfunction were noted, in association with prominent renal infiltration by macrophages and myofibroblasts, along with increased renal abundance of TLR4, IL-6, and IL1β. Regression of functional and structural changes occurred on Day 30. However, the renal content of IL-1β was still elevated at this time, while the local renin-angiotensin system remained activated, and interstitial fibrosis became evident. On Day 180, recurring albuminuria and mild glomerulosclerosis were seen, along with ISCH and unabated interstitial fibrosis, whereas macrophage infiltration was still evident. GT-induced AKI activates innate immunity and promotes renal inflammation. Persistence of these abnormalities provides a plausible explanation for the transition of AKI to CKD observed in a growing number of patients.
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Affiliation(s)
- Amanda Helen Albino
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Orestes Foresto-Neto
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Karin Carneiro Oliveira
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Victor Ferreira Ávila
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Simone Costa Alarcon Arias
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Antonio Carlos Seguro
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Niels Olsen Saraiva Camara
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.,Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Clarice Kazue Fujihara
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Roberto Zatz
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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Veiras LC, Shen JZY, Bernstein EA, Regis GC, Cao D, Okwan-Duodu D, Khan Z, Gibb DR, Dominici FP, Bernstein KE, Giani JF. Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC. J Am Soc Nephrol 2021; 32:1131-1149. [PMID: 33731332 PMCID: PMC8259671 DOI: 10.1681/asn.2020081112] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/21/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. METHODS Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. RESULTS Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti-IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. CONCLUSIONS The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
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Affiliation(s)
- Luciana C. Veiras
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Justin Z. Y. Shen
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ellen A. Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Giovanna C. Regis
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - DuoYao Cao
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Derick Okwan-Duodu
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Zakir Khan
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - David R. Gibb
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Fernando P. Dominici
- Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Kenneth E. Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jorge F. Giani
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California,Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
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11
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De Miguel C, Pelegrín P, Baroja-Mazo A, Cuevas S. Emerging Role of the Inflammasome and Pyroptosis in Hypertension. Int J Mol Sci 2021; 22:ijms22031064. [PMID: 33494430 PMCID: PMC7865380 DOI: 10.3390/ijms22031064] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.
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Affiliation(s)
- Carmen De Miguel
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Correspondence: (C.D.M.); (S.C.); Tel.: +34-868-885031 (S.C.)
| | - Pablo Pelegrín
- Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; (P.P.); (A.B.-M.)
| | - Alberto Baroja-Mazo
- Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; (P.P.); (A.B.-M.)
| | - Santiago Cuevas
- Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; (P.P.); (A.B.-M.)
- Correspondence: (C.D.M.); (S.C.); Tel.: +34-868-885031 (S.C.)
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12
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Lin CY, Wu CH, Hsu CY, Chen TH, Lin MS, Lin YS, Su YJ. Reduced Mortality Associated With the Use of Metformin Among Patients With Autoimmune Diseases. Front Endocrinol (Lausanne) 2021; 12:641635. [PMID: 33967957 PMCID: PMC8104028 DOI: 10.3389/fendo.2021.641635] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/06/2021] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE Metformin has been linked to anti-proliferative and anti-inflammatory mechanisms. In this study, we aimed to examine the long-term impact of metformin on mortality and organ damage in patients with autoimmune diseases and type 2 diabetes mellitus (T2DM). METHODS We conducted a cohort study using the National Health Insurance Research Database in Taiwan between 1997 and 2013. Based on metformin and other anti-diabetic agent prescriptions, we categorized all patients with autoimmune diseases into either the metformin group (metformin administration for at least 28 days) or the non-metformin group. The primary outcomes were all-cause mortality and annual admission rate, while the secondary outcome was target organ damage. We followed patients from the index date to the date on which the event of interest occurred, death, or the end of this study. RESULTS Our cohort study included 3,359 subjects for analysis. During a mean follow up of 5.2 ± 3.8 years, the event rate of all-cause mortality was 228 (33.6%) in the metformin group and 125 (36.9%) in the non-metformin group. The risk of both all-cause mortality and annual number of admissions for autoimmune diseases was significantly lower in the metformin group than in the non-metformin group [hazard ratio (HR) 0.77; 95% CI 0.62-0.96 and risk ratio (RR) 0.81; 95% CI 0.73-0.90, respectively]. CONCLUSION Metformin may add benefits beyond T2DM control with regard to reducing all-cause mortality and admission rate, as well as minimizing end-organ injury in lungs and kidneys among patients with autoimmune diseases.
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Affiliation(s)
- Chun-Yu Lin
- Division of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hsin Wu
- Division of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Yuan Hsu
- Division of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tien-Hsing Chen
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ming-Shyan Lin
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Cardiology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Yu-Sheng Lin
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yu-Jih Su
- Division of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Center for Mitochondrial Research and Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- *Correspondence: Yu-Jih Su,
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13
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Justina VD, Giachini FR, Sullivan JC, Webb RC. Toll-Like Receptors Contribute to Sex Differences in Blood Pressure Regulation. J Cardiovasc Pharmacol 2020; 76:255-266. [PMID: 32902942 PMCID: PMC7751064 DOI: 10.1097/fjc.0000000000000869] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) play an important role in the innate immune system, and recently, they have been shown to be involved in the regulation of blood pressure. The incidence of hypertension is higher in men, and it increases in postmenopausal women. In fact, premenopausal women are protected from cardiovascular disease compared with age-matched men, and it is well established that this protective effect is lost with menopause. However, the molecular mechanisms underlying this protection in women are unknown. Whether or not it could be related to differential activation of the innate immune system remains to be elucidated. This review focuses on (1) the differences between men and women in TLR activation and (2) whether TLR activation may influence the regulation of blood pressure in a sex-dependent manner.
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Affiliation(s)
- Vanessa Dela Justina
- Graduate Program in Biological Sciences, Federal University of Goiás, Goiânia, Brazil
| | - Fernanda R. Giachini
- Graduate Program in Biological Sciences, Federal University of Goiás, Goiânia, Brazil
- Institute of Health Sciences and Health, Universidad Federal De Mato Grosso, Barra Do Garcas, Brazil
| | - Jennifer C. Sullivan
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA
| | - R. Clinton Webb
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA
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14
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Pham GS, Shimoura CG, Chaudhari S, Kulp DV, Mathis KW. Chronic unilateral cervical vagotomy reduces renal inflammation, blood pressure, and renal injury in a mouse model of lupus. Am J Physiol Renal Physiol 2020; 319:F155-F161. [PMID: 32538149 DOI: 10.1152/ajprenal.00201.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is characterized by hypertension that results from chronic renal inflammation and dysautonomia in the form of dampened vagal tone. In health, the vagus nerve regulates inflammatory processes through mechanisms like the cholinergic anti-inflammatory pathway; so in the case of SLE, reduced efferent vagus nerve activity may indirectly affect renal inflammation and therefore hypertension. In this study, we sought to investigate the impact of disrupting vagal neurotransmission on renal inflammation and hypertension in the setting of chronic inflammatory disease. Female SLE (NZBWF1) and control (NZW) mice were subjected to a right unilateral cervical vagotomy or sham surgery and 3 wk later were implanted with indwelling catheters to measure blood pressure. Indices of splenic and renal inflammation, as well as renal injury, were assessed. Unilateral vagotomy blunted SLE-induced increases in mean arterial pressure, albumin excretion rate, and glomerulosclerosis. This protection was associated with reduced splenic T cells and attenuated SLE-induced increases in renal proinflammatory mediators. In summary, these data indicate that unilateral vagotomy reduces renal inflammation and reduces blood pressure in SLE mice. The vagus nerves have myriad functions, and perhaps other neuroimmune interactions compensate for the ligation of one nerve.
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Affiliation(s)
- G S Pham
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas.,Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas
| | - C G Shimoura
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas
| | - S Chaudhari
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas
| | - D V Kulp
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas
| | - K W Mathis
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas
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15
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Krishnan SM, Ling YH, Huuskes BM, Ferens DM, Saini N, Chan CT, Diep H, Kett MM, Samuel CS, Kemp-Harper BK, Robertson AAB, Cooper MA, Peter K, Latz E, Mansell AS, Sobey CG, Drummond GR, Vinh A. Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc Res 2020; 115:776-787. [PMID: 30357309 PMCID: PMC6432065 DOI: 10.1093/cvr/cvy252] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 08/02/2018] [Accepted: 10/22/2018] [Indexed: 11/29/2022] Open
Abstract
Aims Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension. Methods and results C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice. Conclusion MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.
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Affiliation(s)
- Shalini M Krishnan
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Yeong H Ling
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Brooke M Huuskes
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
| | - Dorota M Ferens
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Narbada Saini
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
| | - Christopher T Chan
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Henry Diep
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
| | - Michelle M Kett
- Department of Physiology, Monash University, Clayton, Victoria, Australia
| | - Chrishan S Samuel
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | | | - Avril A B Robertson
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Matthew A Cooper
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Karlheinz Peter
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany.,Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.,German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Ashley S Mansell
- Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Christopher G Sobey
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
| | - Antony Vinh
- Department of Pharmacology, Monash University, Clayton, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne Campus, Bundoora, Victoria, Australia
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16
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Kim S, Jo CH, Kim GH. Effects of empagliflozin on nondiabetic salt-sensitive hypertension in uninephrectomized rats. Hypertens Res 2019; 42:1905-1915. [PMID: 31537914 PMCID: PMC8075936 DOI: 10.1038/s41440-019-0326-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 08/08/2019] [Accepted: 08/22/2019] [Indexed: 12/21/2022]
Abstract
Impaired pressure natriuresis (PN) underlies salt-sensitive hypertension, and renal inflammation and hypoxia-inducible factor-1 (HIF-1) have been implicated in the modulation of systemic hypertension. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors were reported to lower blood pressure (BP) in type 2 diabetes mellitus, whether they have a role in nondiabetic hypertensive kidney diseases is unclear. The present study was undertaken to investigate whether nondiabetic salt-sensitive hypertension and accompanying renal inflammation are ameliorated by SGLT2 inhibition. Male Sprague-Dawley rats were randomly divided into three groups: sham controls (SCs), uninephrectomized controls (UCs), and empagliflozin-treated rats (ETs). All rats were fed a rodent diet with 8% NaCl throughout the study period. Empagliflozin was orally administered for 3 weeks after uninephrectomy. Systolic blood pressure was recorded weekly, and kidneys were harvested for immunoblotting, immunohistochemistry, and quantitative PCR analysis at the end of the animal experiment. Systolic BP was significantly decreased in ETs that were orally given empagliflozin for 3 weeks after uninephrectomy. Although ETs did not show any increase in weekly measured urine sodium, the right-shifted PN relationship in UCs was improved by empagliflozin treatment. The expression of HIF-1α was increased in the renal outer medulla of ETs. Consistent with this, HIF prolyl-hydroxylase-2 protein and mRNA were decreased in ETs. The abundance of CD3 and ED-1 immunostaining in UCs was reduced by empagliflozin treatment. The increased IL-1ß, gp91phox, and NOX4 mRNA levels in UCs were also reversed. Empagliflozin restored impaired PN in nondiabetic hypertensive kidney disease in association with increased renal medullary expression of HIF-1α and amelioration of renal inflammation.
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Affiliation(s)
- Sua Kim
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea
| | - Chor Ho Jo
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea
| | - Gheun-Ho Kim
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea. .,Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.
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17
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Polychronopoulou E, Braconnier P, Burnier M. New Insights on the Role of Sodium in the Physiological Regulation of Blood Pressure and Development of Hypertension. Front Cardiovasc Med 2019; 6:136. [PMID: 31608291 PMCID: PMC6756190 DOI: 10.3389/fcvm.2019.00136] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 08/29/2019] [Indexed: 01/08/2023] Open
Abstract
A precise maintenance of sodium and fluid balance is an essential step in the regulation of blood pressure and alterations of this balance may lead to the development of hypertension. In recent years, several new advances were made in our understanding of the interaction between sodium and blood pressure regulation. The first is the discovery made possible with by new technology, such as 23Na-MRI, that sodium can be stored non-osmotically in tissues including the skin and muscles particularly when subjects are on a high sodium diet or have a reduced renal capacity to excrete sodium. These observations prompted the refinement of the original model of regulation of sodium balance from a two-compartment model comprising the extracellular fluid within the intravascular and interstitial spaces to a three-compartment model that includes the intracellular space of some tissues, most prominently the skin. In this new model, the immune system plays a role, thereby supporting many previous studies indicating that the immune system is a crucial co-contributor to the maintenance of hypertension through pro-hypertensive effects in the kidney, vasculature, and brain. Lastly, there is now evidence that sodium can affect the gut microbiome, and induce pro-inflammatory and immune responses, which might contribute to the development of salt-sensitive hypertension.
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Affiliation(s)
- Erietta Polychronopoulou
- Service of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Philippe Braconnier
- Service of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Michel Burnier
- Service of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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18
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Zambom FFF, Oliveira KC, Foresto-Neto O, Faustino VD, Ávila VF, Albino AH, Arias SCA, Volpini RA, Malheiros DMAC, Saraiva Camara NO, Zatz R, Fujihara CK. Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload. Am J Physiol Renal Physiol 2019; 317:F1058-F1067. [PMID: 31411073 DOI: 10.1152/ajprenal.00251.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide inhibition with Nω-nitro-l-arginine methyl ester (l-NAME), along with salt overload, leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia, and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere have suggested that activation of at least two pathways of innate immunity, Toll-like receptor 4 (TLR4)/NF-κB and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome/IL-1β, occurs in several experimental models of CKD and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-κB or NLRP3/IL-1β pathway, is involved in the pathogenesis of renal injury in chronic nitric oxide inhibition with the salt-overload model. Adult male Munich-Wistar rats that received l-NAME in drinking water with salt overload (HS + N group) were treated with allopurinol (ALLO) as an NLRP3 inhibitor (HS + N + ALLO group) or pyrrolidine dithiocarbamate (PDTC) as an NF-κB inhibitor (HS + N + PDTC group). After 4 wk, HS + N rats developed hypertension, albuminuria, and renal injury along with renal inflammation, oxidative stress, and activation of both the NLRP3/IL-1β and TLR4/NF-κB pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria, and interstitial inflammation/fibrosis but not glomerular injury. PDTC inhibited the renal NF-κB system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1β and TLR4/NF-κB pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection.
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Affiliation(s)
| | - Karin Carneiro Oliveira
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Orestes Foresto-Neto
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Viviane Dias Faustino
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Victor Ferreira Ávila
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Amanda Helen Albino
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Simone Costa Alarcon Arias
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Rildo Aparecido Volpini
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Niels Olsen Saraiva Camara
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.,Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Roberto Zatz
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Clarice Kazue Fujihara
- Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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19
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Gogulamudi VR, Mani I, Subramanian U, Pandey KN. Genetic disruption of Npr1 depletes regulatory T cells and provokes high levels of proinflammatory cytokines and fibrosis in the kidneys of female mutant mice. Am J Physiol Renal Physiol 2019; 316:F1254-F1272. [PMID: 30943067 DOI: 10.1152/ajprenal.00621.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The present study was designed to determine the effects of gene knockout of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) on immunogenic responses affecting kidney function and blood pressure (BP) in Npr1 (coding for GC-A/NPRA)-null mutant mice. We used female Npr1 gene-disrupted (Npr1-/-, 0 copy), heterozygous (Npr1+/-, 1 copy), wild-type (Npr1+/+, 2 copy), and gene-duplicated (Npr1++/++, 4 copy) mice. Expression levels of Toll-like receptor (TLR)2/TLR4 mRNA were increased 4- to 5-fold in 1-copy mice and 6- to 10-fold in 0-copy mice; protein levels were increased 2.5- to 3-fold in 1-copy mice and 4- to 5-fold in 0-copy mice. Expression of proinflammatory cytokines and BP was significantly elevated in 1-copy and 0-copy mice compared with 2-copy and 4-copy mice. In addition, 0-copy and 1-copy mice exhibited drastic reductions in regulatory T cells (Tregs). After rapamycin treatment, Tregs were increased by 17% (P < 0.001) in 0-copy mice and 8% (P < 0.001) in 1-copy mice. Renal mRNA and protein levels of TLR2 and TLR4 were decreased by 70% in 0-copy mice and 50% in 1-copy mice. There were significantly higher levels of Tregs and very low levels of TLR2/TLR4 expression in 4-copy mice (P < 0.001). These findings indicate that the disruption of Npr1 in female mice triggers renal immunogenic pathways, which transactivate the expression of proinflammatory cytokines and renal fibrosis with elevated BP in mutant animals. The data suggest that rapamycin treatment attenuates proinflammatory cytokine expression, dramatically increases anti-inflammatory cytokines, and substantially reduces BP and renal fibrosis in mutant animals.
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Affiliation(s)
| | - Indra Mani
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine , New Orleans, Louisiana
| | - Umadevi Subramanian
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine , New Orleans, Louisiana
| | - Kailash N Pandey
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine , New Orleans, Louisiana
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20
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Eriguchi M, Bernstein EA, Veiras LC, Khan Z, Cao DY, Fuchs S, McDonough AA, Toblli JE, Gonzalez-Villalobos RA, Bernstein KE, Giani JF. The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease. J Am Soc Nephrol 2018; 29:2546-2561. [PMID: 30185469 DOI: 10.1681/asn.2018030323] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/03/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Recent evidence emphasizes the critical role of inflammation in the development of diabetic nephropathy. Angiotensin-converting enzyme (ACE) plays an active role in regulating the renal inflammatory response associated with diabetes. Studies have also shown that ACE has roles in inflammation and the immune response that are independent of angiotensin II. ACE's two catalytically independent domains, the N- and C-domains, can process a variety of substrates other than angiotensin I. METHODS To examine the relative contributions of each ACE domain to the sodium retentive state, renal inflammation, and renal injury associated with diabetic kidney disease, we used streptozotocin to induce diabetes in wild-type mice and in genetic mouse models lacking either a functional ACE N-domain (NKO mice) or C-domain (CKO mice). RESULTS In response to a saline challenge, diabetic NKO mice excreted 32% more urinary sodium compared with diabetic wild-type or CKO mice. Diabetic NKO mice also exhibited 55% less renal epithelial sodium channel cleavage (a marker of channel activity), 55% less renal IL-1β, 53% less renal TNF-α, and 53% less albuminuria than diabetic wild-type mice. This protective phenotype was not associated with changes in renal angiotensin II levels. Further, we present evidence that the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain-specific substrate that accumulates in the urine of NKO mice, mediates the beneficial effects observed in the NKO. CONCLUSIONS These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.
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Affiliation(s)
| | | | | | | | | | - Sebastien Fuchs
- Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, California
| | - Alicia A McDonough
- Department of Integrative Anatomical Sciences, Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Jorge E Toblli
- Laboratory of Experimental Medicine, Hospital Alemán, University of Buenos Aires, National Scientific and Technical Research Council, Buenos Aires, Argentina; and
| | - Romer A Gonzalez-Villalobos
- Departments of Biomedical Sciences and.,Cardiovascular and Metabolism Discovery, Janssen Research and Development, Spring House, Pennsylvania
| | - Kenneth E Bernstein
- Departments of Biomedical Sciences and.,Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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21
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Khan SI, Shihata WA, Andrews KL, Lee MKS, Moore XL, Jefferis AM, Vinh A, Gaspari T, Dragoljevic D, Jennings GL, Murphy AJ, Chin-Dusting JPF. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat. FASEB J 2018; 33:1510-1521. [PMID: 30156911 DOI: 10.1096/fj.201701498rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Despite its well-known antithrombotic properties, the effect of aspirin on blood pressure (BP) and hypertension pathology is unclear. The hugely varying doses used clinically have contributed to this confusion, with high-dose aspirin still commonly used due to concerns about the efficacy of low-dose aspirin. Because prostaglandins have been shown to both promote and inhibit T-cell activation, we also explored the immunomodulatory properties of aspirin in hypertension. Although the common preclinical high dose of 100 mg/kg/d improved vascular dysfunction and cardiac hypertrophy, this effect was accompanied by indices of elevated adaptive immunity, renal T-cell infiltration, renal fibrosis, and BP elevation in stroke-prone spontaneously hypertensive rats and in angiotensin II-induced hypertensive mice. The cardioprotective effects of aspirin were conserved with a lower dose (10 mg/kg/d) while circumventing heightened adaptive immunity and elevated BP. We also show that low-dose aspirin improves renal fibrosis. Differential inhibition of the COX-2 isoform may underlie the disparate effects of the 2 doses. Our results demonstrate the efficacy of low-dose aspirin in treating a vast array of cardiovascular parameters and suggest modulation of adaptive immunity as a novel mechanism underlying adverse cardiovascular profiles associated with COX-2 inhibitors. Clinical studies should identify the dose of aspirin that achieves maximal cardioprotection with a new awareness that higher doses of aspirin could trigger undesired autoimmunity in hypertensive individuals. This work also warrants an evaluation of high-dose aspirin and COX-2 inhibitor therapy in sufferers of inflammatory conditions who are already at increased risk for cardiovascular disease.-Khan, S. I., Shihata, W. A., Andrews, K. L., Lee, M. K. S., Moore, X.-L., Jefferis, A.-M., Vinh, A., Gaspari, T., Dragoljevic, D., Jennings, G. L., Murphy, A. J., Chin-Dusting, J. P. F. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.
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Affiliation(s)
- Shanzana I Khan
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Waled A Shihata
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Karen L Andrews
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Man K S Lee
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Xiao-Lei Moore
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Ann-Maree Jefferis
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Antony Vinh
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Tracey Gaspari
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Dragana Dragoljevic
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Garry L Jennings
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Andrew J Murphy
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Jaye P F Chin-Dusting
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
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22
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Dai X, Hua L, Chen Y, Wang J, Li J, Wu F, Zhang Y, Su J, Wu Z, Liang C. Mechanisms in hypertension and target organ damage: Is the role of the thymus key? (Review). Int J Mol Med 2018; 42:3-12. [PMID: 29620247 PMCID: PMC5979885 DOI: 10.3892/ijmm.2018.3605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 03/27/2018] [Indexed: 12/23/2022] Open
Abstract
A variety of cells and cytokines have been shown to be involved in the whole process of hypertension. Data from experimental and clinical studies on hypertension have confirmed the key roles of immune cells and inflammation in the process. Dysfunction of the thymus, which modulates the development and maturation of lymphocytes, has been shown to be associated with the severity of hypertension. Furthermore, gradual atrophy, functional decline or loss of the thymus has been revealed to be associated with aging. The restoration or enhancement of thymus function via upregulation in the expression of thymus transcription factors forkhead box N1 or thymus transplantation may provide an option to halt or reverse the pathological process of hypertension. Therefore, the thymus may be key in hypertension and associated target organ damage, and may provide a novel treatment strategy for the clinical management of patients with hypertension in addition to different commercial drugs. The purpose of this review is to summarize and discuss the advances in our understanding of the impact of thymus function on hypertension from data from animal and human studies, and the potential mechanisms.
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Affiliation(s)
| | | | | | - Jiamei Wang
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jingyi Li
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Feng Wu
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Yanda Zhang
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jiyuan Su
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Zonggui Wu
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Chun Liang
- Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
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23
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Lopez Gelston CA, Balasubbramanian D, Abouelkheir GR, Lopez AH, Hudson KR, Johnson ER, Muthuchamy M, Mitchell BM, Rutkowski JM. Enhancing Renal Lymphatic Expansion Prevents Hypertension in Mice. Circ Res 2018; 122:1094-1101. [PMID: 29475981 DOI: 10.1161/circresaha.118.312765] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 01/12/2023]
Abstract
RATIONALE Hypertension is associated with renal infiltration of activated immune cells; however, the role of renal lymphatics and immune cell exfiltration is unknown. OBJECTIVE We tested the hypotheses that increased renal lymphatic density is associated with 2 different forms of hypertension in mice and that further augmenting renal lymphatic vessel expansion prevents hypertension by reducing renal immune cell accumulation. METHODS AND RESULTS Mice with salt-sensitive hypertension or nitric oxide synthase inhibition-induced hypertension exhibited significant increases in renal lymphatic vessel density and immune cell infiltration associated with inflammation. Genetic induction of enhanced lymphangiogenesis only in the kidney, however, reduced renal immune cell accumulation and prevented hypertension. CONCLUSIONS These data demonstrate that renal lymphatics play a key role in immune cell trafficking in the kidney and blood pressure regulation in hypertension.
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Affiliation(s)
| | | | | | - Alexandra H Lopez
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Kayla R Hudson
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Eric R Johnson
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Mariappan Muthuchamy
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Brett M Mitchell
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station.
| | - Joseph M Rutkowski
- From the Department of Medical Physiology, Texas A&M College of Medicine, College Station
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24
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Buelvas-Jiménez N, Suárez-Useche RJ, Vielma-Guevara JR. NLRP3 inflammasome: A therapeutic option for kidney disease? ACTA ACUST UNITED AC 2017; 19:118-122. [PMID: 30137165 DOI: 10.15446/rsap.v19n1.54415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 12/08/2016] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To determine if considering inflammasome NLRP3 as a treatment option for kidney disease is possible. METHODS Literature review related to NLRP3 inflammasome structure, biological function and relationship with renal disease and others (hypertension, diabetes, gout, atherosclerosis, amyloidosis, Alzheimer's disease); the systematic review was made searching in the databases PubMed and SciELO for the following terms: "The NLRP3 inflammasome therapeutic for kidney disease", "NLRP3 nflammasome in kidney disease" in PubMed, and "Inflammasome" for Scielo. RESULTS 146 documents were found, althoughonly 34 matched the working hypothesis concerning the NLRP3 inflammasome as a central component of various diseases in humans, with potential therapeutic use. The NLRP3 inflammasome is responsible for the maturation of inflammatory pro-interleukin IL-1 β and IL-18, which can be triggered by aggregated or crystalline materials (particles), and by various microorganisms and toxins derived from these; however, the way how activation mechanisms work is not completely clear. CONCLUSIONS Research on new therapies that focus on removing or inhibiting inflammasome components, both individually and together, is proposed.
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Affiliation(s)
- Neudo Buelvas-Jiménez
- Lic. Biología. M.Sc. en Biología Celular. Laboratorio de Inmunobiología, Centro de Investigaciones Biomédicas (CIB), Instituto Venezolano de Investigaciones Científicas (IVIC), Hospital Universitario de Maracaibo. Maracaibo, Venezuela.
| | - Raibel J Suárez-Useche
- Lic. Bioanálisis. M. Sc. en Biología Molecular. Laboratorio de Inmunobiología, Centro de Investigaciones Biomédicas (CIB), Instituto Venezolano de Investigaciones Científicas (IVIC), Hospital Universitario de Maracaibo. Maracaibo, Venezuela.
| | - José R Vielma-Guevara
- Lic. Bioanálisis. M. Sc. en Biología Celular. Laboratorio de Neurobiología, Centro de Investigaciones Biomédicas (CIB), Instituto Venezolano de Investigaciones Científicas (IVIC), Hospital Universitario de Maracaibo. Maracaibo, Venezuela.
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25
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Ling YH, Krishnan SM, Chan CT, Diep H, Ferens D, Chin-Dusting J, Kemp-Harper BK, Samuel CS, Hewitson TD, Latz E, Mansell A, Sobey CG, Drummond GR. Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. Pharmacol Res 2016; 116:77-86. [PMID: 27986554 DOI: 10.1016/j.phrs.2016.12.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 12/12/2016] [Accepted: 12/12/2016] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. METHODS Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. RESULTS By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. CONCLUSION Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain.
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Affiliation(s)
- Yeong Hann Ling
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Shalini M Krishnan
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Christopher T Chan
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Henry Diep
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Dorota Ferens
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Jaye Chin-Dusting
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Barbara K Kemp-Harper
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia
| | - Timothy D Hewitson
- Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School,Worcester, Massachusetts, USA; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Ashley Mansell
- Hudson Institute of Medical Research, Clayton, Australia
| | - Christopher G Sobey
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Department of Surgery, School of Clinical Sciences, Monash Health, Clayton, Australia
| | - Grant R Drummond
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Department of Surgery, School of Clinical Sciences, Monash Health, Clayton, Australia.
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26
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Manucha W, Juncos LI. The protective role of vitamin D on the heart and the kidney. Ther Adv Cardiovasc Dis 2016; 11:1753944716675820. [PMID: 27784812 DOI: 10.1177/1753944716675820] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
For a long time, vitamin D was regarded as an essential component for the maintenance of appropriate calcium metabolism. Indeed, the calcium-related functions were broadly studied and validated in numerous clinical and epidemiologic studies. All of these vitamin D effects are mediated by a specific receptor. Remarkably, recent investigations show that the vitamin D receptor (VDR) also affects autoimmunity and by these means, the course of neoplasias and tissue inflammation. Moreover, the VDR regulates genes that affect cellular activity including cell differentiation and apoptosis and, by these means, angiogenesis. Actually, vitamin D deficiency has been associated with structural and functional cardiovascular changes that can be reversed by receptor stimulation. In this regard, some of the injurious effects of vitamin D deficiency such as myocardial hypertrophy and high blood pressure seem linked to increased renin-angiotensin activity. Interestingly, chronic renal disease, a condition often associated with greater cardiovascular risk, high blood pressure, myocardial hypertrophy and inappropriate stimulation of the renin angiotensin system, is also tied to inadequate vitamin D activity. In fact, studies in several animal models such as the rat ureteral obstruction model, the 5/6 nephrectomy model and others, clearly show that VDR stimulation prevents both structural and functional changes in the heart and the kidney. Clinical trials are needed to validate the vitamin D potential benefits in chronic kidney disease and its associated cardiovascular risk.
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Affiliation(s)
- Walter Manucha
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Mendoza, Argentina Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Luis I Juncos
- Fundación J. Robert Cade, Pedro de Oñate 253-Córdoba 5003, Argentina
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27
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McDonough AA. ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure-Hypertension and the Proximal Tubule. Kidney Int Rep 2016; 1:166-176. [PMID: 27840855 PMCID: PMC5102061 DOI: 10.1016/j.ekir.2016.06.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Renal control of effective circulating volume (ECV) is key for circulatory performance. When renal sodium excretion is inadequate, blood pressure rises and serves as a homeostatic signal to drive natriuresis to re-establish ECV. Recognizing that hypertension involves both renal and vascular dysfunction, this report concerns proximal tubule sodium hydrogen exchanger 3 (NHE3) regulation during acute and chronic hypertension. NHE3 is distributed in tall microvilli (MV) in the proximal tubule, where it reabsorbs a significant fraction of the filtered sodium. NHE3 redistributes, in the plane of the MV membrane, between the MV body, where NHE3 is active, and the MV base, where NHE3 is less active. A high-salt diet and acute hypertension both retract NHE3 to the base and reduce proximal tubule sodium reabsorption independent of a change in abundance. The renin angiotensin system provokes NHE3 redistribution independent of blood pressure: The angiotensin-converting enzyme (ACE) inhibitor captopril redistributes NHE3 to the base and subsequent angiotensin II (AngII) infusion returns NHE3 to the body of the MV and restores reabsorption. Chronic AngII infusion presents simultaneous AngII stimulation and hypertension; that is, NHE3 remains in the body of the MV, due to the high local AngII level and inflammation, and exhibits a compensatory decrease in abundance driven by the hypertension. Genetically modified mice with blunted hypertensive responses to chronic AngII infusion (due to lack of the proximal tubule AngII receptors interleukin-17A or interferon-γ expression) exhibit reduced local AngII accumulation and inflammation and larger decreases in NHE3 abundance, which improves the pressure natriuresis response and reduces the need for elevated blood pressure to facilitate circulating volume balance.
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Affiliation(s)
- Alicia A McDonough
- Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California
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Tamma G, Valenti G. Evaluating the Oxidative Stress in Renal Diseases: What Is the Role for S-Glutathionylation? Antioxid Redox Signal 2016; 25:147-64. [PMID: 26972776 DOI: 10.1089/ars.2016.6656] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
SIGNIFICANCE Reactive oxygen species (ROS) have long been considered as toxic derivatives of aerobic metabolism displaying a harmful effect to living cells. Deregulation of redox homeostasis and production of excessive free radicals may contribute to the pathogenesis of kidney diseases. In line, oxidative stress increases in patients with renal dysfunctions due to a general increase of ROS paralleled by impaired antioxidant ability. RECENT ADVANCES Emerging evidence revealed that physiologically, ROS can act as signaling molecules interplaying with several transduction pathways such as proliferation, differentiation, and apoptosis. ROS can exert signaling functions by modulating, at different layers, protein oxidation since proteins have "cysteine switches" that can be reversibly reduced or oxidized, supporting the dynamic signaling regulation function. In this scenario, S-glutathionylation is a posttranslational modification involved in oxidative cellular response. CRITICAL ISSUES Although it is widely accepted that renal dysfunctions are often associated with altered redox signaling, the relative role of S-glutathionylation on the pathogenesis of specific renal diseases remains unclear and needs further investigations. In this review, we discuss the impact of ROS in renal health and diseases and the role of selective S-glutathionylation proteins potentially relevant to renal physiology. FUTURE DIRECTIONS The paucity of studies linking the reversible protein glutathionylation with specific renal disorders remains unmet. The growing number of S-glutathionylated proteins indicates that this is a fascinating area of research. In this respect, further studies on the association of reversible glutathionylation with renal diseases, characterized by oxidative stress, may be useful to develop new pharmacological molecules targeting protein S-glutathionylation. Antioxid. Redox Signal. 25, 147-164.
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Affiliation(s)
- Grazia Tamma
- 1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .,2 Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) , Rome, Italy
| | - Giovanna Valenti
- 1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari , Bari, Italy .,2 Istituto Nazionale di Biostrutture e Biosistemi (I.N.B.B.) , Rome, Italy .,3 Centro di Eccellenza di Genomica in campo Biomedico ed Agrario (CEGBA) , Bari, Italy
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29
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Impact of Salt Intake on the Pathogenesis and Treatment of Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 956:61-84. [DOI: 10.1007/5584_2016_147] [Citation(s) in RCA: 173] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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30
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Krishnan SM, Dowling JK, Ling YH, Diep H, Chan CT, Ferens D, Kett MM, Pinar A, Samuel CS, Vinh A, Arumugam TV, Hewitson TD, Kemp-Harper BK, Robertson AAB, Cooper MA, Latz E, Mansell A, Sobey CG, Drummond GR. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. Br J Pharmacol 2015; 173:752-65. [PMID: 26103560 DOI: 10.1111/bph.13230] [Citation(s) in RCA: 157] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 05/16/2015] [Accepted: 06/13/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1β and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1β and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS 1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1β, as well as protein levels of active caspase-1 and mature IL-1β. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1β pathway as a potential therapeutic target in hypertension.
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Affiliation(s)
- S M Krishnan
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - J K Dowling
- Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia
| | - Y H Ling
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - H Diep
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - C T Chan
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - D Ferens
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - M M Kett
- Department of Physiology, Monash University, Clayton, Vic., Australia
| | - A Pinar
- Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia
| | - C S Samuel
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - A Vinh
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - T V Arumugam
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - T D Hewitson
- Department of Nephrology, Royal Melbourne Hospital, Parkville, Vic., Australia
| | - B K Kemp-Harper
- Department of Pharmacology, Monash University, Clayton, Vic., Australia
| | - A A B Robertson
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - M A Cooper
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - E Latz
- Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.,Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.,German Center for Neurodegenerative Diseases, Bonn, Germany
| | - A Mansell
- Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Vic., Australia
| | - C G Sobey
- Department of Pharmacology, Monash University, Clayton, Vic., Australia.,Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Vic., Australia
| | - G R Drummond
- Department of Pharmacology, Monash University, Clayton, Vic., Australia.,Department of Surgery, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, Vic., Australia
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Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR. IL-1β and IL-18: inflammatory markers or mediators of hypertension? Br J Pharmacol 2015; 171:5589-602. [PMID: 25117218 PMCID: PMC4290704 DOI: 10.1111/bph.12876] [Citation(s) in RCA: 168] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 07/30/2014] [Accepted: 08/06/2014] [Indexed: 12/11/2022] Open
Abstract
Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.
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Affiliation(s)
- S M Krishnan
- Department of Pharmacology, Monash University, Clayton, Vic, Australia
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Giani JF, Bernstein KE, Janjulia T, Han J, Toblli JE, Shen XZ, Rodriguez-Iturbe B, McDonough AA, Gonzalez-Villalobos RA. Salt Sensitivity in Response to Renal Injury Requires Renal Angiotensin-Converting Enzyme. Hypertension 2015; 66:534-42. [PMID: 26150439 DOI: 10.1161/hypertensionaha.115.05320] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 06/15/2015] [Indexed: 12/24/2022]
Abstract
Recent evidence indicates that salt-sensitive hypertension can result from a subclinical injury that impairs the kidneys' capacity to properly respond to a high-salt diet. However, how this occurs is not well understood. Here, we showed that although previously salt-resistant wild-type mice became salt sensitive after the induction of renal injury with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride; mice lacking renal angiotensin-converting enzyme, exposed to the same insult, did not become hypertensive when faced with a sodium load. This is because the activity of renal angiotensin-converting enzyme plays a critical role in (1) augmenting the local pool of angiotensin II and (2) the establishment of the antinatriuretic state via modulation of glomerular filtration rate and sodium tubular transport. Thus, this study demonstrates that the presence of renal angiotensin-converting enzyme plays a pivotal role in the development of salt sensitivity in response to renal injury.
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Affiliation(s)
- Jorge F Giani
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Kenneth E Bernstein
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Tea Janjulia
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Jiyang Han
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Jorge E Toblli
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Xiao Z Shen
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Bernardo Rodriguez-Iturbe
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Alicia A McDonough
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.)
| | - Romer A Gonzalez-Villalobos
- From the Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA (J.F.G., K.E.B., T.J., X.Z.S., R.A.G.-V.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (J.H., A.A.M.); Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina (J.E.T.); Servicio de Nefrología, Hospital Universitario de Maracaibo, Maracaibo, Venezuela (B.R.-I.); and Physiology Group, DSRD/Global Safety Pharmacology, Pfizer Inc., Groton, CT (R.A.G.-V.).
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Abstract
A powerful interaction between the autonomic and the immune systems plays a prominent role in the initiation and maintenance of hypertension and significantly contributes to cardiovascular pathology, end-organ damage and mortality. Studies have shown consistent association between hypertension, proinflammatory cytokines and the cells of the innate and adaptive immune systems. The sympathetic nervous system, a major determinant of hypertension, innervates the bone marrow, spleen and peripheral lymphatic system and is proinflammatory, whereas the parasympathetic nerve activity dampens the inflammatory response through α7-nicotinic acetylcholine receptors. The neuro-immune synapse is bidirectional as cytokines may enhance the sympathetic activity through their central nervous system action that in turn increases the mobilization, migration and infiltration of immune cells in the end organs. Kidneys may be infiltrated by immune cells and mesangial cells that may originate in the bone marrow and release inflammatory cytokines that cause renal damage. Hypertension is also accompanied by infiltration of the adventitia and perivascular adipose tissue by inflammatory immune cells including macrophages. Increased cytokine production induces myogenic and structural changes in the resistance vessels, causing elevated blood pressure. Cardiac hypertrophy in hypertension may result from the mechanical afterload and the inflammatory response to resident or migratory immune cells. Toll-like receptors on innate immune cells function as sterile injury detectors and initiate the inflammatory pathway. Finally, abnormalities of innate immune cells and the molecular determinants of their activation that include toll-like receptor, adrenergic, cholinergic and AT1 receptors can define the severity of inflammation in hypertension. These receptors are putative therapeutic targets.
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Meng H, Liu G, Zhai J, Zhen Y, Zhao Q, Zheng M, Ma G, Wang L, Tian L, Ji L, Duan L, Li L, Liu K, Liu C. Prednisone in Uric Acid Lowering in Symptomatic Heart Failure Patients with Hyperuricemia — The PUSH-PATH3 Study. J Rheumatol 2015; 42:866-9. [DOI: 10.3899/jrheum.141037] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2015] [Indexed: 01/18/2023]
Abstract
Objective.To determine the safety and efficacy of prednisone in patients with symptomatic heart failure (HF) and hyperuricemia.Methods.Prednisone therapy was administered for a short time to 191 symptomatic HF patients with hyperuricemia (serum uric acid > 7 mg/dl).Results.Prednisone significantly reduced serum uric acid by 2.99 mg/dl (p < 0.01) and serum creatinine by 0.17 mg/dl (p < 0.01). These favorable effects were associated with a remarkable increase in urine output, improvement in renal function, and improvement in clinical status.Conclusion.Prednisone can be used safely in symptomatic HF patients with hyperuricemia.
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35
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Javkhedkar AA, Quiroz Y, Rodriguez-Iturbe B, Vaziri ND, Lokhandwala MF, Banday AA. Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2015; 308:R840-6. [PMID: 25761698 DOI: 10.1152/ajpregu.00308.2014] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 03/06/2015] [Indexed: 01/02/2023]
Abstract
Compelling evidence supports the role of oxidative stress and renal interstitial inflammation in the pathogenesis of hypertension. Resveratrol is a polyphenolic stilbene, which can lower oxidative stress by activating the transcription factor nuclear factor-E2-related factor-2 (Nrf2), the master regulator of numerous genes encoding antioxidant and phase II-detoxifying enzymes and molecules. Given the role of oxidative stress and inflammation in the pathogenesis of hypertension, we conducted this study to test the hypothesis that long-term administration of resveratrol will attenuate renal inflammation and oxidative stress and, hence, progression of hypertension in the young spontaneously hypertensive rats (SHR). SHR and control [Wistar-Kyoto (WKY)] rats were treated for 9 wk with resveratrol or vehicle in their drinking water. Vehicle-treated SHR exhibited renal inflammatory injury and oxidative stress, as evidenced by glomerulosclerosis, tubulointerstitial injury, infiltration of inflammatory cells, and increased levels of renal 8-isoprostane and protein carbonylation. This was associated with reduced antioxidant capacity and downregulations of Nrf2 and phase II antioxidant enzyme glutathione-S-transferase (GST). Resveratrol treatment mitigated renal inflammation and injury, reduced oxidative stress, normalized antioxidant capacity, restored Nrf2 and GST activity, and attenuated the progression of hypertension in SHR. However, resveratrol had no effect on these parameters in WKY rats. In conclusion, development and progression of hypertension in the SHR are associated with inflammation, oxidative stress, and impaired Nrf2-GST activity in the kidney. Long-term administration of resveratrol restores Nrf2 expression, ameliorates inflammation, and attenuates development of hypertension in SHR. Clinical studies are needed to explore efficacy of resveratrol in human hypertension.
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Affiliation(s)
- Apurva A Javkhedkar
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston Texas
| | - Yasmir Quiroz
- Hospital Universitario, Universidad del Zulia and Instituto Venezolano de Investigaciones Científicas-Zulia, Maracaibo, Venezuela; and
| | - Bernardo Rodriguez-Iturbe
- Hospital Universitario, Universidad del Zulia and Instituto Venezolano de Investigaciones Científicas-Zulia, Maracaibo, Venezuela; and
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, California
| | - Mustafa F Lokhandwala
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston Texas
| | - Anees A Banday
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston Texas;
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Kamat NV, Thabet SR, Xiao L, Saleh MA, Kirabo A, Madhur MS, Delpire E, Harrison DG, McDonough AA. Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice. Hypertension 2015; 65:569-76. [PMID: 25601932 DOI: 10.1161/hypertensionaha.114.04975] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration, and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically interferon-γ (IFN-γ) and interleukin-17A (IL-17A), to sodium transporter regulation in the kidney during angiotensin-II (Ang-II) hypertension. C57BL/6J (wild-type) mice responded to Ang-II infusion (490 ng/kg per minute, 2 weeks) with a rise in blood pressure (170 mm Hg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ(-/-)) or IL-17A (IL-17A(-/-)) exhibited a blunted rise in blood pressure (<150 mm Hg), and both the genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, Ang-II infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter, and Ste20/SPS-1-related proline-alanine-rich kinase, in both the wild-type and the IL-17A(-/-) but not in IFN-γ(-/-) mice; epithelial Na channel abundance increased similarly in all the 3 genotypes. In the proximal nephron, Ang-II infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A(-/-) and IFN-γ(-/-), but not in wild-type; the Na-phosphate cotransporter decreased in all the 3 genotypes. Our results suggest that during Ang-II hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.
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Affiliation(s)
- Nikhil V Kamat
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Salim R Thabet
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Liang Xiao
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Mohamed A Saleh
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Annet Kirabo
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Meena S Madhur
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Eric Delpire
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - David G Harrison
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.)
| | - Alicia A McDonough
- From the Department of Cell and Neurobiology, Keck School of Medicine of USC, Los Angeles, CA (N.V.K., A.A.M.); Division of Clinical Pharmacology, Department of Medicine (S.R.T., L.X., M.A.S., A.K., M.S.M., D.G.H.) and Department of Anesthesiology (E.D.), Vanderbilt University School of Medicine, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.).
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Mathis KW, Wallace K, Flynn ER, Maric-Bilkan C, LaMarca B, Ryan MJ. Preventing autoimmunity protects against the development of hypertension and renal injury. Hypertension 2014; 64:792-800. [PMID: 25024282 DOI: 10.1161/hypertensionaha.114.04006] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production, and the prevalence of hypertension is increased markedly in this patient population compared with normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or immunoglobulin G antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein-1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation are an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus.
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Affiliation(s)
- Keisa W Mathis
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson
| | - Kedra Wallace
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson
| | - Elizabeth R Flynn
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson
| | - Christine Maric-Bilkan
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson
| | - Babbette LaMarca
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson
| | - Michael J Ryan
- From the Departments of Physiology and Biophysics (K.W.M., E.R.F., C.M.-B., M.J.R.), Obstetrics and Gynecology (K.W.), and Pharmacology and Toxicology (B.L.), University of Mississippi Medical Center, Jackson.
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Pollow DP, Uhrlaub J, Romero-Aleshire M, Sandberg K, Nikolich-Zugich J, Brooks HL, Hay M. Sex differences in T-lymphocyte tissue infiltration and development of angiotensin II hypertension. Hypertension 2014; 64:384-390. [PMID: 24890822 DOI: 10.1161/hypertensionaha.114.03581] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
There is extensive evidence that activation of the immune system is both necessary and required for the development of angiotensin II (Ang II)-induced hypertension in males. The purpose of this study was to determine whether sex differences exist in the ability of the adaptive immune system to induce Ang II-dependent hypertension and whether central and renal T-cell infiltration during Ang II-induced hypertension is sex dependent. Recombinant activating gene-1 (Rag-1)(-/-) mice, lacking both T and B cells, were used. Male and female Rag-1(-/-) mice received adoptive transfer of male CD3(+) T cells 3 weeks before 14-day Ang II infusion (490 ng/kg per minute). Blood pressure was monitored via tail cuff. In the absence of T cells, systolic blood pressure responses to Ang II were similar between sexes (Δ22.1 mm Hg males versus Δ18 mm : Hg females). After adoptive transfer of male T cells, Ang II significantly increased systolic blood pressure in males (Δ37.7 mm : Hg; P<0.05) when compared with females (Δ13.7 mm : Hg). Flow cytometric analysis of total T cells and CD4(+), CD8(+), and regulatory Foxp3(+)-CD4(+) T-cell subsets identified that renal lymphocyte infiltration was significantly increased in males versus females in both control and Ang II-infused animals (P<0.05). Immunohistochemical staining for CD3(+)-positive T cells in the subfornical organ region of the brain was increased in males when compared with that in females. These results suggest that female Rag-1(-/-) mice are protected from male T-cell-mediated increases in Ang II-induced hypertension when compared with their male counterparts, and this protection may involve sex differences in the magnitude of T-cell infiltration of the kidney and brain.
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Affiliation(s)
- Dennis P Pollow
- Department of Physiology University of Arizona, Tucson, AZ.,Sarver Heart Center University of Arizona, Tucson, AZ
| | | | | | - Kathryn Sandberg
- Department of Medicine and Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, DC
| | | | - Heddwen L Brooks
- Department of Physiology University of Arizona, Tucson, AZ.,Sarver Heart Center University of Arizona, Tucson, AZ
| | - Meredith Hay
- Department of Physiology University of Arizona, Tucson, AZ.,Sarver Heart Center University of Arizona, Tucson, AZ.,Evelyn McKnight Brain Institute, University of Arizona, Tucson, AZ
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Integrin-linked kinase plays a key role in the regulation of angiotensin II-induced renal inflammation. Clin Sci (Lond) 2014; 127:19-31. [PMID: 24383472 DOI: 10.1042/cs20130412] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ILK (integrin-linked kinase) is an intracellular serine/threonine kinase involved in cell-matrix interactions. ILK dysregulation has been described in chronic renal disease and modulates podocyte function and fibrosis, whereas data about its role in inflammation are scarce. AngII (angiotensin II) is a pro-inflammatory cytokine that promotes renal inflammation. AngII blockers are renoprotective and down-regulate ILK in experimental kidney disease, but the involvement of ILK in the actions of AngII in the kidney has not been addressed. Therefore we have investigated whether ILK signalling modulates the kidney response to systemic AngII infusion in wild-type and ILK-conditional knockout mice. In wild-type mice, AngII induced an inflammatory response, characterized by infiltration of monocytes/macrophages and lymphocytes, and up-regulation of pro-inflammatory factors (chemokines, adhesion molecules and cytokines). AngII activated several intracellular signalling mechanisms, such as the NF-κB (nuclear factor κB) transcription factor, Akt and production of ROS (reactive oxygen species). All these responses were prevented in AngII-infused ILK-deficient mice. In vitro studies characterized further the mechanisms regulating the inflammatory response modulated by ILK. In cultured tubular epithelial cells ILK blockade, by siRNA, inhibited AngII-induced NF-κB subunit p65 phosphorylation and its nuclear translocation. Moreover, ILK gene silencing prevented NF-κB-related pro-inflammatory gene up-regulation. The results of the present study demonstrate that ILK plays a key role in the regulation of renal inflammation by modulating the canonical NF-κB pathway, and suggest a potential therapeutic target for inflammatory renal diseases.
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Doi T, Doi S, Nakashima A, Ueno T, Yokoyama Y, Kohno N, Masaki T. Mizoribine ameliorates renal injury and hypertension along with the attenuation of renal caspase-1 expression in aldosterone-salt-treated rats. PLoS One 2014; 9:e93513. [PMID: 24695748 PMCID: PMC3973594 DOI: 10.1371/journal.pone.0093513] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 03/07/2014] [Indexed: 12/01/2022] Open
Abstract
Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group): (1) vehicle infusion group, (2) aldosterone infusion group, or (3) aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.
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Affiliation(s)
- Toshiki Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shigehiro Doi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Toshinori Ueno
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yukio Yokoyama
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Nobuoki Kohno
- Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
- * E-mail:
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Abstract
One in every three adults in the United States has hypertension, and the underlying cause of most of these cases is unknown. Therefore, it is imperative to continue the study of mechanisms involved in the pathogenesis of hypertension. Decades ago, studies speculated that elements of an autoimmune response were associated with the development of hypertension based, in part, on the presence of circulating autoantibodies in hypertensive patients. In the past decade, a growing number of studies have been published supporting the concept that self-antigens and the subsequent activation of the adaptive immune system promote the development of hypertension. This manuscript will provide a brief review of the evidence supporting a role for the immune system in the development of hypertension, studies that implicate both cell-mediated and humoral immunity, and the relevance of understanding blood pressure control in an autoimmune disease model with hypertension.
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Affiliation(s)
- Keisa W Mathis
- Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216-4505, USA
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Renal molecular mechanisms underlying altered Na+ handling and genesis of hypertension during adulthood in prenatally undernourished rats. Br J Nutr 2014; 111:1932-44. [PMID: 24661554 DOI: 10.1017/s0007114513004236] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the present study, we investigated the development of hypertension in prenatally undernourished adult rats, including the mechanisms that culminate in dysfunctions of molecular signalling in the kidney. Dams were fed a low-protein multideficient diet throughout gestation with or without α-tocopherol during lactation. The time course of hypertension development followed in male offspring was correlated with alterations in proximal tubule Na+-ATPase activity, expression of angiotensin II (Ang II) receptors, and activity of protein kinases C and A. After the establishment of hypertension, Ang II levels, cyclo-oxygenase 2 (COX-2) and NADPH oxidase subunit expression, lipid peroxidation and macrophage infiltration were examined in renal tissue. Lipid peroxidation in undernourished rats, which was very intense at 60 d, decreased at 90 d and returned to control values by 150 d. During the prehypertensive phase, prenatally undernourished rats exhibited elevated renal Na+-ATPase activity, type 2 Ang II receptor down-regulation and altered protein kinase A:protein kinase C ratio. Stable late hypertension coexisted with highly elevated levels of Ang II-positive cells in the cortical tubulointerstitium, enhanced increase in the expression of p47phox (NADPH oxidase regulatory subunit), marked down-regulation of COX-2 expression, expanded plasma volume and decreased creatinine clearance. These alterations were reduced when the dams were given α-tocopherol during lactation. The offspring of well-nourished dams treated with α-tocopherol exhibited most of the alterations encountered in the offspring of undernourished dams not treated with α-tocopherol. Thus, alterations in proximal tubule Na+ transport, subcellular signalling pathways and reactive oxygen species handling in renal tissue underpin the development of hypertension.
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Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol 2014; 6:38-66. [PMID: 24575172 PMCID: PMC3935060 DOI: 10.4330/wjc.v6.i2.38] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/22/2013] [Accepted: 12/17/2013] [Indexed: 02/06/2023] Open
Abstract
Vascular biology, endothelial and vascular smooth muscle and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients can prevent, control and treat hypertension through numerous mechanisms related to vascular biology. Oxidative stress, inflammation and autoimmune dysfunction initiate and propagate hypertension and cardiovascular disease. There is a role for the selected use of single and component nutraceutical supplements, vitamins, antioxidants and minerals in the treatment of hypertension based on scientifically controlled studies which complement optimal nutrition, coupled with other lifestyle modifications.
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Affiliation(s)
- Mark Houston
- Mark Houston, Hypertension Institute, Saint Thomas Medical Plaza, Nashville, TN 37205, United States
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Procalcitonin and the inflammatory response to salt in essential hypertension: a randomized cross-over clinical trial. J Hypertens 2014; 31:1424-30; discussion 1430. [PMID: 23743803 DOI: 10.1097/hjh.0b013e328360ddd5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVES Inflammation is considered as a major effector of arterial damage brought about by salt excess in animal models. In a randomized, single masked, cross-over study in 32 uncomplicated essential hypertensive patients, we assessed the effect of a short-term low-salt diet on biomarkers of innate immunity [procalcitonin (PCT), interleukin-6, C-reactive protein, and tumor necrosis factor-α (TNF-α)], adiponectin (ADPN, an anti-inflammatory cytokine), and leptin. METHODS Patients were randomized to either a 10-20 mmol sodium diet and sodium tablets (180 mEq/day) to achieve a 200 mmol intake per day or the same diet and identical placebo tablets, each for 2 weeks. At the end of each of these periods, all patients underwent a 24-h urine collection, a fasting blood sampling, and a 24 h ambulatory blood pressure monitoring. RESULTS In parallel with expected increase in plasma renin activity and aldosterone (P<0.001), both PCT (+33%) and TNF-α (9%) rose at low salt intake (P≤0.007) while ADPN underwent an opposite change (- 17%, P<0.001). In a linear regression analysis for repeated measurements, PCT was significantly and inversely related to urinary salt (weighted r=-0.27, P=0.03). Changes in inflammation biomarkers did not differ in salt-sensitive (n=7) and salt-resistant (n=25) patients. CONCLUSION In essential hypertensive patients, a very low salt diet generates a pro-inflammatory phenotype characterized by an increase in PCT and TNF-α and an opposite effect on an anti-inflammatory cytokine like ADPN.
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Rudemiller N, Lund H, Jacob HJ, Geurts AM, Mattson DL. CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 2013; 63:559-64. [PMID: 24343121 DOI: 10.1161/hypertensionaha.113.02191] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The CD3 ζ chain (CD247), a gene involved in T-cell signaling, has been shown to associate with blood pressure in human genetic studies. To test the functional role of CD247 in hypertension and renal disease, zinc-finger nucleases targeting CD247 were injected into Dahl salt-sensitive (SS/JrHsdMcwi) embryos. The resulting 11-bp frameshift deletion in exon 1 of CD247 led to a predicted premature stop codon. Western blotting confirmed the absence of CD247 protein in the thymus, and flow cytometry (n=5-9 per group) demonstrated that the mutant rats (CD247(-/-)) have a >99% reduction in circulating CD3(+) T cells compared with littermate controls (CD247(+/+)). Studies were performed on age-matched, littermate male, CD247(+/+) and CD247(-/-) rats fed a 4.0% NaCl diet for 3 weeks. The infiltration of CD3(+) T cells into the kidney after high salt was significantly blunted in CD247(-/-) (1.4±0.4×10(5) cells per kidney) when compared with that in the CD247(+/+) (8.7±2.0×10(5) cells per kidney). Accompanying the reduced infiltration of T cells, mean arterial blood pressure was significantly lower in CD247(-/-) than in CD247(+/+) (134±1 versus 151±2 mm Hg). As an index of kidney disease, urinary albumin and protein excretion rates were significantly reduced in CD247(-/-) (17±1 and 62±2 mg/d, respectively) when compared with that in CD247(+/+) (49±3 and 121±5 mg/d, respectively). Glomerular and renal tubular damage were also attenuated in the CD247(-/-). These studies demonstrate that functional T cells are required for the full development of Dahl salt-sensitive hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function.
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Affiliation(s)
- Nathan Rudemiller
- Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
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Kriska T, Cepura C, Gauthier KM, Campbell WB. Role of macrophage PPARγ in experimental hypertension. Am J Physiol Heart Circ Physiol 2013; 306:H26-32. [PMID: 24163073 DOI: 10.1152/ajpheart.00287.2013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Targeted disruption of the Alox15 gene makes mice resistant to angiotensin II-, DOCA/salt-, and N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced experimental hypertension. Macrophages, a primary source of Alox15, are facilitating this resistance, but the underlying mechanism is not known. Because Alox15 metabolites are peroxisome proliferator-activated receptor (PPAR)γ agonists, we hypothesized that activation of macrophage PPARγ is the key step in Alox15 mediation of hypertension. Thioglycollate, used for macrophage elicitation, selectively upregulated PPARγ and its target gene CD36 in peritoneal macrophages of both wild-type (WT) and Alox15(-/-) mice. Moreover, thioglycollate-injected Alox15(-/-) mice became hypertensive upon L-NAME treatment. A similar hypertensive effect was observed with adoptive transfer of thioglycollate-elicited Alox15(-/-) macrophages into Alox15(-/-) recipient mice. The role of PPARγ was further specified by using the selective PPARγ antagonist GW9662. WT mice treated with 50 μg/kg daily dose of GW9662 for 12 days became resistant to L-NAME-induced hypertension. The PPARγ antagonist treatment also prevented L-NAME-induced hypertension in thioglycollate-injected Alox15(-/-) mice, indicating a PPARγ-mediated effect in macrophage elicitation and the resultant hypertension. These results indicate a regulatory role for macrophage-localized PPARγ in L-NAME-induced experimental hypertension.
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Affiliation(s)
- Tamas Kriska
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
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48
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Houston M. Nutrition and nutraceutical supplements for the treatment of hypertension: part I. J Clin Hypertens (Greenwich) 2013; 15:752-7. [PMID: 24088285 PMCID: PMC8033896 DOI: 10.1111/jch.12188] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/19/2013] [Accepted: 07/21/2013] [Indexed: 12/16/2022]
Abstract
Vascular biology, endothelial and vascular smooth muscle, and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease, and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients may be able to prevent, control, or treat hypertension through numerous mechanisms related to vascular biology or other mechanisms. Oxidative stress, inflammation, and autoimmune dysfunction are some of the primary factors that initiate and propagate hypertension and cardiovascular disease. The literature suggests that there may be a complementary role of single and component nutraceutical supplements, vitamins, antioxidants, and minerals in the treatment of hypertension when combined with optimal nutrition and other lifestyle modifications. However, many of these studies are small and do not have long-term follow-up for efficacy and safety. The role of these nutrition and nutraceutical supplements will require careful review and additional studies to determine their exact role in the management of hypertension.
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Affiliation(s)
- Mark Houston
- Department of Medicine, Vanderbilt University School of Medicine, Hypertension Institute of Nashville, Saint Thomas Medical Group and Health ServicesSaint Thomas HospitalNashvilleTN
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Jin K, Vaziri ND. Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation. Clin Exp Nephrol 2013; 18:445-52. [PMID: 23933891 DOI: 10.1007/s10157-013-0851-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 07/30/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND Renal interstitial inflammation and oxidative stress are invariably present and play a key role in the pathogenesis of hypertension in experimental animals. Mitochondria are the major source of reactive oxygen species (ROS). ROS generated in the mitochondria are normally contained by the mitochondrial antioxidant system including manganese superoxide dismutase (MnSOD). We have previously shown that a high salt diet causes hypertension in MnSOD-deficient (MnSOD(+/-)) mice but not in wild-type mice. The present study was undertaken to determine the effect of a high salt diet on oxidative and inflammatory pathways in the kidneys of MnSOD(+/-) mice compared to the wild-type mice. METHODS Wild-type (MnSOD(+/+)) and MnSOD(+/-) mice were randomized to receive a regular or a high salt diet for 4 months. Tail arterial pressure was measured and timed urine collection was obtained. The animals were then euthanized and the kidneys were harvested and processed for histological examination and Western blot analyses. RESULTS In confirmation of our earlier study, a high salt diet resulted in a significant rise in arterial pressure and urinary albumin excretion in MnSOD(+/-) mice. This was accompanied by upregulation of NAD(P)H oxidase subunits, activation of nuclear factor kappa B, and elevation of PAI-1, iNOS, oxidized LDL receptor, and CD36 in the kidneys of the MnSOD(+/-) mice fed the high salt diet. In contrast, consumption of a high salt diet did not significantly alter blood pressure, urine protein excretion, or the measured oxidative and inflammatory mediators in the wild-type mice. CONCLUSION Salt-induced hypertension in MnSOD(+/-) mice is associated with activation of intra-renal inflammatory and ROS generating pathways.
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Affiliation(s)
- Kyubok Jin
- Division of Nephrology and Hypertension, University of California, Irvine, Irvine, CA, USA,
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50
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Whiting C, Castillo A, Haque MZ, Majid DSA. Protective role of the endothelial isoform of nitric oxide synthase in ANG II-induced inflammatory responses in the kidney. Am J Physiol Renal Physiol 2013; 305:F1031-41. [PMID: 23926180 DOI: 10.1152/ajprenal.00024.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-α. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O2(-)) scavenger, tempol (400 mg/l in the drinking water), or a TNF-α receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Δ36 ± 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Δ24 ± 3 mmHg; n = 6). In KO mice (n = 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (Δ17 ± 7 mmHg; n = 6) but exaggeratedly in KO (Δ48 ± 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol (n = 6) or etanercept (n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II.
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Affiliation(s)
- Curtis Whiting
- Dept. of Physiology, Hypertension and Renal Center of Excellence, Tulane Univ. Health Sciences Center, New Orleans, LA 70112, USA.
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