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Intrarenal activation of renin angiotensin system in the development of cyclosporine A induced chronic nephrotoxicity

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Chinese Medical Journal 2008年第11期121卷 983-988页

作者： SHANG Ming-hua YUAN Wei-jie ZHANG Shu-jian FAN Yu ZHANG Zheng Department of Nephrology First People's HospitalShanghai Jiaotong University Shanghai 200080 China Department of Nephrology Qingdao Municipal Hospital QingdaoShandong 266011 China Organs Transplantation Centre First People's HospitalShanghai Jiaotong University Shanghai 200080 China

Background The relationship between cyclosporine-induced chronic nephrotoxicity （CAN） and renin-angiotenein II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II （ANGII） both in renal tissue and plasma from kidney transplantation patients suffering from CAN. Methods Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity （CAN group） and chronic rejection （control group） were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose （C2）. In vitro, human umbilical vein endothelial cells （HUVEC） and rat mesangial cells （MC） were incubated with different concentrations of CsA （0, 250, 500, 1000 μg/L） for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining. Results Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls （P 〈0.05）. The plasma levels of renin, ANGII and C2 in the CAN group were higher than the control group, but no significant difference was found （（0.37±0.12） ng·ml^-1·h^-1 vs （0.20±0.10） ng·ml^-1·h^-1, P=0.076; （122.69±26.73） pg/ml vs （121.88±36.35） pg/ml, P=0.977; （719.04±55.89） ng/ml vs （658.80±90.78） ng/ml, P=0.196, respectively）. In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours （P 〈0.05）. CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner. Conclusions Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal renin angiotensin system plays an important role in CsA-related ch

关键词： cyclosporine toxicity renin-angiotensin system kidney transplantation

The renin-angiotensin system,mood,and suicide:Are there associations?

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World Journal of Psychiatry 2021年第9期11卷 581-588页

作者： Marsal Sanches Antonio Lucio Teixeira UT Center of Excellence on Mood Disorders Department of Psychiatry and Behavioral SciencesThe University of Texas Health Science Center at HoustonHoustonTX 77054United States UT Health Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at HoustonHoustonTX 77054United States

Available evidence points to a possible role of the renin-angiotensin system(RAS)in the pathophysiology of mood disorders and suicide.We carried out a critical analysis of literature data regarding this role,with a focus on the proposed association between RAS dysfunction and suicidal behavior.Epidemiological,genetic,and biochemical findings are described,and the pathophysiological hypothesis aiming at explaining the possible relationship between RAS and suicide are discussed.Available findings do support the involvement of the RAS in the neurobiology of suicide,although the exact mechanisms underlying this involvement are still unknown.

关键词： renin-angiotensin system Suicide Mood disorders Depression Bipolar disorder

Postnatal renin-angiotensin system inhibition prevents renal damage from prenatal inflammation in rats

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Journal of Traditional Chinese Medicine 2020年第4期40卷 646-653页

作者： Guo Wei Ji Yan Han Qi Yang Yao Wang Fangjie Yang Yongjian Deng Youcai Sun Xiongshan Li Xiaohui Institute of Materia Medica College of Pharmacy and Department of PharmacySouthwest HospitalArmy Medical University(Third Military Medical University)Chongqing 400038China Department of Cardiology The General Hospital of Western Theater Command(Chengdu Military General Hospital)Chengdu 610083China

OBJECTIVE:To assess the protective role of benazepril,an angiotensin-converting enzyme inhibitor,in renal damage caused by prenatal inflammation.METHODS:Saline or lipopolysaccharide were administered intraperitoneally to pregnant Sprague-Dawley rats on gestation days 8,10,and 12.After birth,offspring received either tap water or benazepril in water between 7 and 68 weeks.Blood pressure,blood urea nitrogen,creatinine,and 24-h urine volume were measured as indices of renal function.Hematoxylin,eosin,periodic acid-Schiff,and Sirius Red staining were used to evaluate renal damage.RESULTS:Postnatal benazepril treatment ameliorated hypertension and restored normal 24-h urine volume and blood urea nitrogen and serum creatinine levels.Benazepril treatment also reduced glycoprotein accumulation and fibrosis in the glomerulus and in tubular epithelial cells and inhibited nuclear factor-kappa B activation.CONCLUSION:Together with our previous findings that postnatal inhibition of nuclear factor-kappa B activation blocks intra-renal renin-angiotensin system activation,our current data demonstrate that intra-renal activation of the renin-angiotensin system interacts with nuclear factor-kappa B activation to cause renal damage in adulthood following prenatal inflammation.

关键词： renin-angiotensin system NF-kappa B Benazepril Prenatal inflammatory exposure

angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis:Should we consider further implications?

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World Journal of Gastroenterology 2024年第18期30卷 2391-2396页

作者： Michele Barone Section of Gastroenterology Department of Precision and Regenerative Medicine-Jonian Area-University of BariBari 70124Italy

This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology.The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis.Here,we recapitulated the complexity of the renin-angiotensin system,discussed the role of hepatic stellate cell(HSC)autophagy in liver fibrogenesis,and analyzed the possible implications in the development of hepatocarcinoma(HCC).angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis,whereas their involvement in HCC is more evident in experimental conditions than in human studies.angiotensin-converting enzyme 2(ACE2),and its product angiotensin(Ang)1-7,not only regulate HSC autophagy and liver fibrosis,but they also represent potential targets for unexplored applications in the field of HCC.Finally,ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR)pathway.In this case,Ang 1-7 acts binding to the MasR,and its agonists could modulate this pathway.However,since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively,we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

关键词： renin-angiotensin system Liver fibrosis Hepatic stellate cells Autophagy Hepatocellular carcinoma

Cancer stem cell subpopulations in metastatic melanoma to the brain express components of the renin-angiotensin system

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Journal of Cancer Metastasis and Treatment 2019年第8期4卷 12-20页

作者： Agadha C.Wickremesekera Helen D.Brasch Valerie M.Lee Paul F.Davis Andrew Parker Helge Koeck Tinte Itinteang Swee T.Tan Gillies McIndoe Research Institute Wellington 6242New Zealand Department of Neurosurgery Wellington Regional HospitalWellington 6021New Zealand Wellington Regional Plastic Maxillofacial&Burns UnitHutt HospitalWellingtonLower Hutt 5010New Zealand.

Aim: There is increasing appreciation of the role of the renin-angiotensin system (RAS) in carcinogenesis with recent evidence showing expression of the RAS by cancer stem cells (CSCs) in different types of cancer. We have recently demonstrated the presence of three CSC subpopulations within metastatic melanoma (MM) to the brain: a Melan-A+ subpopulation and a Melan-A- subpopulation within the tumor that express OCT4, SALL4, SOX2 and NANOG;and a pSTAT3+ subpopulation localized to the CD34+ endothelium of microvessels within the tumor. In this study we investigated the expression and localization of components of the RAS in relation to these CSCs in MM to the brain. Methods: 3, 3-diaminobenzidine immunohistochemical (IHC) staining of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin Ⅱ receptor 1 (ATIIR1) and angiotensin Ⅱ receptor 2 (ATIIR2) was performed on the same ten samples of MM to the brain included in our previous study. Immunofluorescence IHC staining of these components of the RAS was performed with embryonic stem cell markers OCT4 and NANOG, and endothelial marker CD34, on two of the samples of MM to the brain from the original cohort of ten patients. Western blotting (n = 5) and NanoString mRNA analysis (n = 4) were performed on samples of MM to the brain to confirm protein and mRNA expression of these components of the RAS, respectively. Results: DAB IHC staining showed the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten samples of MM to the brain. IF IHC staining showed that the CSC subpopulations in MM to the brain expressed PRR, ATIIR1 and ATIIR2;and a CSC subpopulation on the endothelium of the microvessels expressed ACE. Western blotting and NanoString mRNA analysis confirmed protein and mRNA expression of these components of the RAS, respectively. Conclusion: CSCs in MM to the brain expressed components of the RAS. Targeting the CSCs using modulators of the RAS may be a novel therapeutic approach for treating this aggressive cancer.

关键词： Malignant melanoma metastatic cancer stem cells renin-angiotensin system cancer brain

Ocular renin-angiotensin system with special reference in the anterior part of the eye

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World Journal of Ophthalmology 2015年第3期5卷 110-124页

作者： Mervi Holappa Heikki Vapaatalo Anu Vaajanen BioMediTech University of Tampere Institute of Biomedicine PharmacologyUniversity of Helsinki Department of Ophthalmology Tampere University Hospital SILK Department of OphthalmologySchool of MedicineUniversity of Tampere

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

关键词： angiotensin converting enzyme 1 angiotensin converting enzyme 2 angiotensin converting enzyme-inhibitors angiotensinⅡ angiotensin(1-9) angiotensin(1-7) Glaucoma Intraocular pressure renin-angiotensin system

renin angiotensin system Components and Cancer: Reports of Association

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Journal of Biosciences and Medicines 2016年第5期4卷 65-75页

作者： Maria Del Carmen Garcia Molina Wolgien Silvana Aparecida Alves Correa Pedro Alexandre Federico Breuel Afonso Celso Pinto Nazário Gil Facina Division of Mastology Department of Gynecology Federal University of Sao Paulo Paulista School of Medicine (UNIFESP-EPM) Sao Paulo Brazil Division of Mastology Departament of Gynecology Municipal Hospital and Maternity School Vila Nova Cachoeirinha Sao Paulo Brazil Division of Plastic Surgery Department of Surgery Federal University of Sao Paulo Paulista School of Medicine (UNIFESP-EPM) Sao Paulo Brazil Facvest University Center (UNIFACVEST) Post-Graduation Public Health Division Lages Santa Catarina Brazil Department of Teaching and Research Municipal Hospital and Maternity School Vila Nova Cachoeirinha Sao Paulo Brazil

renin-angiotensin system (RAS) is involved with hypertension and other cardiovascular diseases. However, the association of RAS components to cancer still causes suspicion. To try to clarify this, here we aimed to show this association for three important components: angiotensin Converting Enzyme 1 (ACE1), angiotensin Type 1 Receptor (AGTR1) and angiotensin Type 2 Receptor (AGTR2). The first articles show that association of RAS components with cancer dates back to the 70’s. ECA1 and AGTR1 have close association with cancer and ACE1 inhibitors or AGTR1 blockers are candidates to treatment of some tumors. Moreover, the action of AGTR2 is still controversial, but most studies show that the increased expression of AGTR2 can attack the cancer cells. In breast cancer, these components have also been widely studied and many works have shown that the correlation exists. Therefore specific target using these RAS components could be a beneficial, novel therapy to various tumors.

关键词： renin-angiotensin system angiotensin Converting Enzyme angiotensin Type 1 Receptor angiotensin Type 2 Receptor Breast Cancer Cancer

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

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Journal of Cancer Metastasis and Treatment 2019年第4期4卷 162-172页

作者： Anantha Narayanan Susrutha K.Wickremesekera Bede van Schaijik Reginald W.Marsh Helen D.Brasch Swee T.Tan Tinte Itinteang Gillies McIndoe Research Institute Wellington 6242New Zealand Upper Gastrointestinal Hepatobiliary&Pancreatic SectionDepartment of General SurgeryWellington Regional HospitalWellington 6242New Zealand University of Auckland Auckland 1010New Zealand Wellington Regional Plastic Maxillofacial&Burns UnitHutt HospitalWellington 6242New Zealand

Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB,n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively. Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS. ;Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

关键词： Cancer stem cells colorectal colon cancer adenocarcinoma liver metastasis renin-angiotensin system

Cholesterol loading activates intracellular renin-angiotensin system in human renal mesangial cells:a potential mechanism for glomerulosclerosis

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Cholesterol loading activates intracellular renin-angiotensi...