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1
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Vergès B. Cardiovascular disease in type 1 diabetes, an underestimated danger: Epidemiological and pathophysiological data. Atherosclerosis 2024; 394:117158. [PMID: 37369617 DOI: 10.1016/j.atherosclerosis.2023.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023]
Abstract
Cardiovascular disease (CV) is a common complication of type 1 diabetes (T1D) and a leading cause of death. T1D patients are more likely to develop CV disease (CVD) early in life and show a reduction of life expectancy of at least 11 years. Patients with a young age of T1D onset have a substantially higher CV risk. The reasons for increased atherosclerosis in T1D patients are not entirely explained. In addition to the typical CV risk factors, long-term hyperglycemia has a significant impact by inducing oxidative stress, vascular inflammation, monocyte adhesion, arterial wall thickening and endothelial dysfunction. Additionally, CVD in T1D is also associated with nephropathy. However, CVD risk is still significantly increased in T1D patients, in good glycemic control without additional CV risk factors, indicating the involvement of supplementary potential factors. By increasing oxidative stress, vascular inflammation, and endothelial dysfunction, hypoglycemia and glucose variability may exacerbate CVD. Moreover, significant qualitative and functional abnormalities of lipoproteins are present in even well-controlled T1D patients and are likely to play a role in the development of atherosclerosis and the promotion of CVD. According to recent research, immune system dysfunction, which is typical of auto-immune T1D, may also promote CVD, likely via inflammatory pathways. In addition, T1D patients who are overweight or obese exhibit an additional CV risk due to pathophysiological mechanisms that are similar to those seen in T2D.
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Affiliation(s)
- Bruno Vergès
- Endocrinology-Diabetology Department, University-Hospital of Dijon, Dijon, France; INSERM LNC-UMR1231, Medicine University, 21000 Dijon, France; Service Endocrinologie, Diabétologie et Maladies Métaboliques, CHU-Dijon, 14 rue Gaffarel, F-21000 Dijon, France.
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2
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Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
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Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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3
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Liu Y, Lv Y, Zhang T, Huang T, Lang Y, Sheng Q, Liu Y, Kong Z, Gao Y, Lu S, Yang M, Luan Y, Wang X, Lv Z. T cells and their products in diabetic kidney disease. Front Immunol 2023; 14:1084448. [PMID: 36776877 PMCID: PMC9909022 DOI: 10.3389/fimmu.2023.1084448] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/02/2023] [Indexed: 01/27/2023] Open
Abstract
Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease and has gradually become a public health problem worldwide. DKD is increasingly recognized as a comprehensive inflammatory disease that is largely regulated by T cells. Given the pivotal role of T cells and T cells-producing cytokines in DKD, we summarized recent advances concerning T cells in the progression of type 2 diabetic nephropathy and provided a novel perspective of immune-related factors in diabetes. Specific emphasis is placed on the classification of T cells, process of T cell recruitment, function of T cells in the development of diabetic kidney damage, and potential treatments and therapeutic strategies involving T cells.
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Affiliation(s)
- Yue Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yaodong Lv
- Department of Neurology, Yantai Yuhuangding Hospital, Shandong University, Yantai, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tongtong Huang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yating Lang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qinghao Sheng
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yingxiao Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhijuan Kong
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ying Gao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shangwei Lu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Meilin Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yaqi Luan
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xining Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Nishad R, Mukhi D, Kethavath S, Raviraj S, Paturi ASV, Motrapu M, Kurukuti S, Pasupulati AK. Podocyte derived TNF-α mediates monocyte differentiation and contributes to glomerular injury. FASEB J 2022; 36:e22622. [PMID: 36421039 DOI: 10.1096/fj.202200923r] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/31/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022]
Abstract
Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Macrophage accumulation predicts the severity of kidney injury in human biopsies and experimental models of DKD. However, the mechanism underlying macrophage recruitment in diabetes glomeruli is unclear. Elevated plasma growth hormone (GH) levels in type I diabetes and acromegalic individuals impaired glomerular biology. In this study, we examined whether GH-stimulated podocytes contribute to macrophage accumulation. RNA-seq analysis revealed elevated TNF-α signaling in GH-treated human podocytes. Conditioned media from GH-treated podocytes (GH-CM) induced differentiation of monocytes to macrophages. On the other hand, neutralization of GH-CM with the TNF-α antibody diminished GH-CM's action on monocytes. The treatment of mice with GH resulted in increased macrophage recruitment, podocyte injury, and proteinuria. Furthermore, we noticed the activation of TNF-α signaling, macrophage accumulation, and fibrosis in DKD patients' kidney biopsies. Our findings suggest that podocytes could secrete TNF-α and contribute to macrophage migration, resulting in DKD-related renal inflammation. Inhibition of either GH action or TNF-α expression in podocytes could be a novel therapeutic approach for DKD treatment.
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Affiliation(s)
- Rajkishor Nishad
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Srinivas Kethavath
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sumathi Raviraj
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Atreya S V Paturi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Manga Motrapu
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sreenivasulu Kurukuti
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Anil Kumar Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
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5
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Qin W, Yang Z, Yin J, Chen D, Huo J, Wang J, Wang L, Zhuo Q. Effect Assessment of Aurantio-Obtusin on Novel Human Renal Glomerular Endothelial Cells Model Using a Microfluidic Chip. Nutrients 2022; 14:4615. [PMID: 36364876 PMCID: PMC9654768 DOI: 10.3390/nu14214615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/28/2022] [Accepted: 10/29/2022] [Indexed: 02/02/2024] Open
Abstract
Cassiae semen is widely used as a raw material of health food. Anthraquinone compounds, the main components in cassiae semen, have been reported to show nephrotoxicity. Aurantio-obtusin (AO) is a major anthraquinone compound extracted from cassiae semen. This study investigates the effects of AO on the morphology and physiological function of human renal glomerular endothelial cells (HRGECs) on a microfluidic chip device for the first time. HRGECs were cultured on a microfluidic plate and exposed to a series of AO concentrations. Compared with traditional 96-well culture, HRGECs cultured on the microfluidic chip appeared to better mimic the glomerular microenvironment in vivo. AO induced different degrees of damage to cellular morphology and physiological function. The leakage of lactate dehydrogenase (LDH), as well as the secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and monocyte chemoattractant protein 1 (MCP-1), increased in the AO treated groups. At the same time, cell viability and expression of ZO-1 in the AO treated groups decreased in a dose-dependent manner. The innovative device enables direct visualization and quantification to evaluate the cytotoxic effects of AO on HRGECs, and provides a useful visual in vitro model for studying health effect of health food.
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Affiliation(s)
- Wen Qin
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Zhuo Yang
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Jiyong Yin
- Department of Food Science and Technology, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Di Chen
- Department of Food Science and Technology, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Junsheng Huo
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Jingbo Wang
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Liyuan Wang
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
| | - Qin Zhuo
- Department of Central Laboratory, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
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6
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Wang Z, Chen Z, Wang X, Hu Y, Kong J, Lai J, Li T, Hu B, Zhang Y, Zheng X, Liu X, Wang S, Ye S, Zhou Q, Zheng C. Sappanone a prevents diabetic kidney disease by inhibiting kidney inflammation and fibrosis via the NF-κB signaling pathway. Front Pharmacol 2022; 13:953004. [PMID: 36052141 PMCID: PMC9426375 DOI: 10.3389/fphar.2022.953004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/01/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Low grade of sterile inflammation plays detrimental roles in the progression of diabetic kidney disease (DKD). Sappanone A (SA), a kind of homoisoflavanone isolated from the heartwood of Caesalpinia sappan, exerts anti-inflammatory effects in acute kidney injury. However, whether SA has beneficial effects on diabetic kidney disease remains further exploration. Methods and Results: In the present study, uninephrectomized male mice were treated with Streptozotocin (STZ, 50 mg/kg) for five consecutive days to induce diabetes. Next, the diabetic mice were administered orally with SA (10, 20, or 30 mg/kg) or vehicle once per day. Our results showed that STZ treatment significantly enhanced damage in the kidney, as indicated by an increased ratio of kidney weight/body weight, elevated serum creatinine and blood urea nitrogen (BUN), as well as increased 24-h urinary protein excretion, whereas SA-treated mice exhibited a markedly amelioration in these kidney damages. Furthermore, SA attenuated the pathological changes, alleviated fibrotic molecules transforming growth factor-β1 (TGF-β1) and Collagen-IV (Col-IV) production, decreased inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression in STZ-treated mice. Similarly, in glomerular mesangial cells, SA pretreatment decreased high glucose (HG)-induced proliferation, inflammatory cytokines excretion, and fibrotic molecules expression. Mechanistically, SA decreased the expression of nuclear factor kappa B (NF-κB) and restored the expression of total NF-κB inhibitor alpha (IκBα) both in vivo and in vitro. Conclusion: Our data suggest that SA may prevent diabetes-induced kidney inflammation and fibrosis by inhibiting the NF-κB pathway. Hence, SA can be potential and specific therapeutic value in DKD.
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Affiliation(s)
- Zhe Wang
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhida Chen
- Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyi Wang
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yepeng Hu
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Kong
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiabin Lai
- Department of Pathology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tiekun Li
- Nanjing Kingmed Center for Clinical Laboratory Co., Ltd., Nanjing, China
| | - Bibi Hu
- Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yikai Zhang
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xianan Zheng
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoxian Liu
- Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengyao Wang
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shu Ye
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qiao Zhou
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Zheng
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Chao Zheng,
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7
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Advancements in nanomedicines for the detection and treatment of diabetic kidney disease. BIOMATERIALS AND BIOSYSTEMS 2022; 6:100047. [PMID: 36824160 PMCID: PMC9934479 DOI: 10.1016/j.bbiosy.2022.100047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/22/2022] [Accepted: 03/27/2022] [Indexed: 12/18/2022] Open
Abstract
In the diabetic kidneys, morbidities such as accelerated ageing, hypertension and hyperglycaemia create a pro-inflammatory microenvironment characterised by extensive fibrogenesis. Radiological techniques are not yet optimised generating inconsistent and non-reproducible data. The gold standard procedure to assess renal fibrosis is kidney biopsy, followed by histopathological assessment. However, this method is risky, invasive, subjective and examines less than 0.01% of kidney tissue resulting in diagnostic errors. As such, less than 10% of patients undergo kidney biopsy, limiting the accuracy of the current diabetic kidney disease (DKD) staging method. Standard treatments suppress the renin-angiotensin system to control hypertension and use of pharmaceuticals aimed at controlling diabetes have shown promise but can cause hypoglycaemia, diuresis and malnutrition as a result of low caloric intake. New approaches to both diagnosis and treatment are required. Nanoparticles (NPs) are an attractive candidate for managing DKD due to their ability to act as theranostic tools that can carry drugs and enhance image contrast. NP-based point-of-care systems can provide physiological information previously considered unattainable and provide control over the rate and location of drug release. Here we discuss the use of nanotechnology in renal disease, its application to both the treatment and diagnosis of DKD. Finally, we propose a new method of NP-based DKD classification that overcomes the current systems limitations.
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8
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Sun L, Sun C, Zhou S, Zhang L, Hu W. Tamsulosin attenuates high glucose- induced injury in glomerular endothelial cells. Bioengineered 2021; 12:5184-5194. [PMID: 34402375 PMCID: PMC8806910 DOI: 10.1080/21655979.2021.1955527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN) is a common complication of diabetes. Tamsulosin is a selective α1-AR antagonist. α1-AR is expressed widely in kidney tissues and has displayed its various physiological functions. However, whether Tamsulosin has affects DN is unknown. To our knowledge, this is the first time it has been examined whether Tamsulosin possesses a beneficial effect in high glucose-challenged glomerular endothelial cells (GECs). Firstly, we found that Tamsulosin reduced high glucose-induced expressions of TNF-α, IL-6, and IL-8. Secondly, Tamsulosin alleviated high glucose-induced expressions of MMP-2 and MMP-9. Thirdly, Tamsulosin inhibited the expressions of VCAM-1 and ICAM-1. Importantly, our results indicate that Tamsulosin inhibited high glucose-induced expressions of fibrosis factors such as Col-1 and TGF-β1. Additionally, we found that Tamsulosin ameliorated oxidative stress via reducing the generation of ROS and preventing the activation of p38. Mechanistically, we found that Tamsulosin attenuated high glucose-induced activation of NF-κB. Based on these findings, we conclude that Tamsulosin could attenuate high glucose-induced injury in GECs through alleviating oxidative stress and inflammatory response.
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Affiliation(s)
- Lin Sun
- Department of Pharmacy Intravenous Admixture Service, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Chengmin Sun
- Department of Traditional Chinese Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shibo Zhou
- Inpatient Department Central Pharmacy, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lan Zhang
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Wenping Hu
- Department of Nephrology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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9
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Medapati JR, Rapaka D, Bitra VR, Ranajit SK, Guntuku GS, Akula A. Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2021. [DOI: 10.1186/s43088-021-00121-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
Background
The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks.
Results
The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001).
Conclusions
From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy.
Graphical abstract
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10
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Donate-Correa J, Ferri CM, Sánchez-Quintana F, Pérez-Castro A, González-Luis A, Martín-Núñez E, Mora-Fernández C, Navarro-González JF. Inflammatory Cytokines in Diabetic Kidney Disease: Pathophysiologic and Therapeutic Implications. Front Med (Lausanne) 2021; 7:628289. [PMID: 33553221 PMCID: PMC7862763 DOI: 10.3389/fmed.2020.628289] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/24/2020] [Indexed: 12/29/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and a main contributing factor for cardiovascular morbidity and mortality in patients with diabetes mellitus. Strategies employed to delay the progression of this pathology focus on the control of traditional risk factors, such as hyperglycemia, and elevated blood pressure. Although the intimate mechanisms involved in the onset and progression of DKD remain incompletely understood, inflammation is currently recognized as one of the main underlying processes. Untangling the mechanisms involved in the appearing of a harmful inflammatory response in the diabetic patient is crucial for the development of new therapeutic strategies. In this review, we focus on the inflammation-related pathogenic mechanisms involved in DKD and in the therapeutic utility of new anti-inflammatory strategies.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
| | - Carla M Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Fátima Sánchez-Quintana
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Atteneri Pérez-Castro
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain.,Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.,GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain.,REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
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11
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Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice. Int J Mol Sci 2020; 21:ijms21207495. [PMID: 33050674 PMCID: PMC7589797 DOI: 10.3390/ijms21207495] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/29/2022] Open
Abstract
Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-β mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.
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12
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Cardiovascular disease in type 1 diabetes: A review of epidemiological data and underlying mechanisms. DIABETES & METABOLISM 2020; 46:442-449. [PMID: 32998054 DOI: 10.1016/j.diabet.2020.09.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/27/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022]
Abstract
Cardiovascular disease (CVD) is highly prevalent in patients with type 1 diabetes (T1D) and a major cause of mortality. CVD arises earlier in life in T1D patients and is responsible for a significant reduction of at least 11 years' life expectancy. Also, the incidence of CVD is much more pronounced in patients with T1D onset at an earlier age. However, the factors responsible for increased atherosclerosis and CVD in T1D are not yet totally clarified. In addition to the usual cardiovascular (CV) risk factors, chronic hyperglycaemia plays an important role by promoting oxidative stress, vascular inflammation, monocyte adhesion, arterial wall thickening and endothelial dysfunction. Diabetic nephropathy and cardiac autonomic neuropathy are also associated with increased CVD in T1D. In fact, the CVD risk remains significantly increased even in well-controlled T1D patients who have no additional CV risk factors, indicating that other potential factors are likely to be involved. Hypoglycemia and glucose variability could enhance CV disease by promoting oxidative stress, vascular inflammation and endothelial dysfunction. Furthermore, even well-controlled T1D patients show significant qualitative and functional abnormalities of lipoproteins that are likely to be implicated in the development of atherosclerosis and premature CVD. In addition, recent data suggest that a dysfunctional immune system, which is typical of autoimmune T1D, might also promote CVD possibly through inflammatory pathways. Moreover, overweight and obese T1D patients can manifest additional CV risk through pathophysiological mechanisms resembling those observed in type 2 diabetes (T2D).
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13
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Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury. Clin Sci (Lond) 2020; 134:403-417. [PMID: 32095833 DOI: 10.1042/cs20190584] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/03/2020] [Accepted: 02/10/2020] [Indexed: 12/25/2022]
Abstract
Diabetic kidney disease is one of the most serious complications of diabetes worldwide and is the leading cause of end-stage renal disease. While research has primarily focused on hyperglycemia as a key player in the pathophysiology of diabetic complications, recently, increasing evidence have underlined the role of adipose inflammation in modulating the development and/or progression of diabetic kidney disease. This review focuses on how adipose inflammation contribute to diabetic kidney disease. Furthermore, it discusses in detail the underlying mechanisms of adipose inflammation, including pro-inflammatory cytokines, oxidative stress, and AMPK/mTOR signaling pathway and critically describes their role in diabetic kidney disease. This in-depth understanding of adipose inflammation and its impact on diabetic kidney disease highlights the need for novel interventions in the treatment of diabetic complications.
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The Mechanism of Contrast-Induced Acute Kidney Injury and Its Association with Diabetes Mellitus. CONTRAST MEDIA & MOLECULAR IMAGING 2020; 2020:3295176. [PMID: 32788887 PMCID: PMC7330652 DOI: 10.1155/2020/3295176] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 05/26/2020] [Indexed: 02/08/2023]
Abstract
Contrast-induced acute kidney injury (CI-AKI) is the third most common hospital-acquired AKI after AKI induced by renal perfusion insufficiency and nephrotoxic drugs, taking great adverse effects on the prognosis and increasing hospital stay and medical cost. Diabetes nephropathy (DN) is a common chronic complication of DM (diabetes mellitus), and DN is an independent risk factor for chronic kidney disease (CKD) and CI-AKI. The incidence of CI-AKI significantly increases in patients with renal injury, especially in DM-related nephropathy. The etiology of CI-AKI is not fully clear, and research studies on how DM becomes a facilitated factor of CI-AKI are limited. This review describes the mechanism from three aspects. ① Pathophysiological changes of CI-AKI in kidney under high-glucose status (HGS). HGS can enhance the oxidative stress and increase ROS which next causes stronger vessel constriction and insufficient oxygen supply in kidney via vasoactive substances. HGS also aggravates some ion pump load and the latter increases oxygen consumption. CI-AKI and HGS are mutually causal, making the kidney function continue to decline. ② Immunological changes of DM promoting CI-AKI. Some innate immune cells and pattern recognition receptors (PRRs) in DM and/or DN may respond to some damage-associated molecular patterns (DAMPs) formed by CI-AKI. These effects overlap with some pathophysiological changes in hyperglycemia. ③ Signaling pathways related to both CI-AKI and DM. These pathways involved in CI-AKI are closely associated with apoptosis, inflammation, and ROS production, and some studies suggest that these pathways may be potential targets for alleviating CI-AKI. In conclusion, the pathogenesis of CI-AKI and the mechanism of DM as a predisposing factor for CI-AKI, especially signaling pathways, need further investigation to provide new clinical approaches to prevent and treat CI-AKI.
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Ibrahim AAS, Morsy MM, Abouhashem SE, Aly O, Sabbah NA, Raafat N. Role of mesenchymal stem cells and their culture medium in alleviating kidney injury in rats diabetic nephropathy. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-00064-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
Diabetic nephropathy (DN) is considered as one of the most serious complications resulting from diabetes mellitus and end-stage of renal failure globally. Up to 40% of diabetic patients will develop DN. The involvement of mesenchymal stem cells (MSCs) in diabetic renal lesions management has been established in many animal models of DN. The aim is to evaluate the capability of MSCs and their culture medium (CM) to alleviate DN in streptozotocin (STZ)-induced diabetic rat model. Female albino rats were made diabetic and were further categorized into 4 subgroups of 15 each: DN group, DN group received fibroblasts, MSCs group received one dose of 1 × 106 cells of MSCs, and CM group received one dose of 500 μl of CM. In all groups, the treatment was delivered by intravenous injection (IV) into the tail vein.
Results
MSCs insinuated themselves into the injured kidney as detected by CD44 expression. Biochemical and histological results showed that MSCs and/or CM effectively attenuated DN manifestations in rat model through their possible anti-inflammatory (tumor necrosis factor-α and transforming growth factor-β1 were decreased), anti-apoptotic (Bcl2 was increased while Bax and caspases were decreased), and anti-oxidant role (malondialdehyde was decreased while glutathione and catalase were increased).
Conclusion
These results provide a potential therapeutic tool for DN management through the administration of the CM from MSCs that ameliorates the effects of diabetes. It is also possible to treat DN using CM alone thus avoiding cell transplantation.
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16
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Donate-Correa J, Luis-Rodríguez D, Martín-Núñez E, Tagua VG, Hernández-Carballo C, Ferri C, Rodríguez-Rodríguez AE, Mora-Fernández C, Navarro-González JF. Inflammatory Targets in Diabetic Nephropathy. J Clin Med 2020; 9:jcm9020458. [PMID: 32046074 PMCID: PMC7074396 DOI: 10.3390/jcm9020458] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/31/2022] Open
Abstract
One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
| | - Desirée Luis-Rodríguez
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | - Víctor G. Tagua
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
| | | | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | | | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38010 San Cristóbal de La Laguna, Spain
- Correspondence: ; Tel.: +34-922-602-389
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17
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Wang HQ, Wang SS, Chiufai K, Wang Q, Cheng XL. Umbelliferone ameliorates renal function in diabetic nephropathy rats through regulating inflammation and TLR/NF-κB pathway. Chin J Nat Med 2020; 17:346-354. [PMID: 31171269 DOI: 10.1016/s1875-5364(19)30040-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Indexed: 12/20/2022]
Abstract
Diabetic nephropathy (DN) is a leading cause of renal failure, contributing to severe morbidity and mortality in diabetic patients. Umbelliferae (Umb) has been well characterized to exert protective effects in diabetes. However, the action and mechanism of Umb in DN remains unclear. In this work, we studied the effect of Umb in a streptozotocin (STZ)-induced DN rat model and explore its underlying mechanism. DN rats were treated withUmb (20, 40 mg·kg-1) orirbesartan (15 mg·kg-1) for 4 weeks. Levels of serum glucose, insulin, blood uric acid, creatinine, triglycerides (TG) and total cholesterol (TC) were measured bycommercial assay kits, respectively. Histopathological changes andinflammatory cytokine levels including IL-6, IL-1β and TNF-α in the kidney were also evaluated. Alterations in the expression of podocin, CD2AP and TLR/NF-κB were assessed by western blotting. Our results showed that Umb reduced renal injury in DN rat model, as evidenced by the decrease in blood glucose, 24 h urinary protein, serum creatinine, and blood uric acid. Umb also significantly ameliorated the renal histopathological alteration, and down-regulated the expression of epithelial-to-mesenchymal transition-related molecular markers podocin and CD2AP. Moreover, Umb inhibited TLR2, TLR4, MyD88 expressions, NF-κB activation and considerably reduced levels of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β). These findings indicated that Umb improved renal function through regulating inflammation and TLR/NF-κB pathway, suggesting the potential efficacy of Umb in DN treatment.
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Affiliation(s)
- Han-Qing Wang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Sha-Sha Wang
- School of Rehabilitation Medicine, Binzhou Medical University, Yantai 264003, China
| | - Kuok Chiufai
- School of Health Sciences, Macao Polytechnic Institute, Macao SAR 999078, China
| | - Qi Wang
- Nanjing Dorra Pharmaceutical Co., Ltd., Nanjing 210012, China.
| | - Xiao-Lan Cheng
- Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
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18
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Su SC, Hung YJ, Huang CL, Shieh YS, Chien CY, Chiang CF, Liu JS, Lu CH, Hsieh CH, Lin CM, Lee CH. Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways. J Biomed Sci 2019; 26:68. [PMID: 31492153 PMCID: PMC6731603 DOI: 10.1186/s12929-019-0550-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 07/25/2019] [Indexed: 02/08/2023] Open
Abstract
Background Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. Objectives In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. Method We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. Results Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. Conclusions Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.
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Affiliation(s)
- Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. .,Division of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
| | - Chia-Luen Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Shing Shieh
- School of Dentistry, National Defense Medical Center, Taipei, Taiwan.,Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.,Division of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Chu-Yen Chien
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Fu Chiang
- School of Dentistry, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Ming Lin
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. .,Division of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
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19
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Rehman MU, Rashid SM, Rasool S, Shakeel S, Ahmad B, Ahmad SB, Madkhali H, Ganaie MA, Majid S, Bhat SA. Zingerone (4-(4-hydroxy-3-methylphenyl)butan-2-one) ameliorates renal function via controlling oxidative burst and inflammation in experimental diabetic nephropathy. Arch Physiol Biochem 2019. [PMID: 29537332 DOI: 10.1080/13813455.2018.1448422] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Development of diabetic nephropathy (DN) is directly linked to oxidative stress and inflammation. In this context, inflammatory and oxidative markers have gained much attention as targets for therapeutic intervention. We studied the effect of zingerone in a streptozotocin/high fat diet (STZ/HFD)-induced type 2 diabetic Wistar rat model. Zingerone also known as vanillyl acetone is a pharmacologically active compound present usually in dry ginger. STZ/HFD caused excessive increase in ROS and inflammation in experimental animals. The treatment with zingerone markedly abrogated ROS levels, inhibited the NF-кB activation and considerably reduced level of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β), furthermore, zingerone treatment improved renal functioning by significantly decreasing the levels of kidney toxicity markers KIM-1, BUN, creatinine, and LDH and suppressed TGF-β. Collectively, these findings indicate that zingerone treatment improved renal function by anti-hyperglycaemic, anti-oxidant, and anti-inflammatory effects, suggesting the efficacy of zingerone in the treatment of DN.
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Affiliation(s)
- Muneeb U Rehman
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Shahzada Mudasir Rashid
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Saiema Rasool
- b Department of Forest ManagementForest Biotech Lab , Universiti Putra Malaysia , Serdang , Malaysia
| | - Sheeba Shakeel
- c Department of Pharmaceutical Sciences , University of Kashmir , Srinagar , India
| | - Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Sheikh Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Hassan Madkhali
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Majid Ahmad Ganaie
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Sabiya Majid
- e Department of Biochemistry , Govt. Medical College , Srinagar , India
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20
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Yaribeygi H, Atkin SL, Sahebkar A. Interleukin-18 and diabetic nephropathy: A review. J Cell Physiol 2018; 234:5674-5682. [PMID: 30417374 DOI: 10.1002/jcp.27427] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/21/2018] [Indexed: 12/17/2022]
Abstract
The inflammatory response has an important role in the pathophysiology of diabetic nephropathy that is contributed to by inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α, and macrophage chemotactic protein-1; however, the role of IL-18 seems to be more specific than other cytokines in the inflammatory process. IL-18 is expressed in renal tissue and is upregulated by several stimuli including hyperglycemia. The expression/urinary level of IL-18 is positively correlated with the progression of diabetic nephropathy and the urinary albumin excretion rate. In this review, we have focused on the molecular pathways modulating the relationship between IL-18 and diabetic nephropathy.
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Affiliation(s)
- Habib Yaribeygi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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21
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Kayano R, Morofuji Y, Nakagawa S, Fukuda S, Watanabe D, Ozawa H, Niwa M, Matsuo T. In vitro analysis of drugs that improve hyperglycemia-induced blood-brain barrier dysfunction. Biochem Biophys Res Commun 2018; 503:1885-1890. [PMID: 30060956 DOI: 10.1016/j.bbrc.2018.07.131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 07/25/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND Blood-brain barrier (BBB) disruptions are a key feature of hyperglycemia (HG)-induced cerebral damage. Patients with diabetes mellitus often have other cerebrovascular disease risk factors including hypertension, dyslipidemia, arrhythmia, and atherosclerosis obliterans. However, whether the drugs for these comorbidities are effective for improving HG-induced BBB damage is unclear. METHODS We investigated the effect of pitavastatin, candesartan, cilostazol, propranolol, and eicosapentaenoic acid on HG-induced BBB damage. In vitro BBB models consisting of primary cultures of rat brain capillary endothelial cells were subjected to HG (55 mM d-glucose). RESULTS We observed a significant decrease in transendothelial electrical resistance (TEER) with HG, showing that HG compromised the integrity of the in vitro BBB model. No significant decrease in cell viability was seen with HG, but HG increased the production of reactive oxygen species. Pitavastatin and candesartan inhibited decreases in TEER induced by HG. CONCLUSIONS In summary, pitavastatin and candesartan improved HG-induced BBB damage and this in vitro model of HG-induced BBB dysfunction contributes to the search for BBB protective drugs.
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Affiliation(s)
- Ryoma Kayano
- Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yoichi Morofuji
- Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Shinsuke Nakagawa
- Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Shuji Fukuda
- Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Daisuke Watanabe
- BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, 1-43 Dejima, Nagasaki, 850-0862, Japan
| | - Hiroki Ozawa
- Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Masami Niwa
- BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, 1-43 Dejima, Nagasaki, 850-0862, Japan; Nagasaki University, Japan
| | - Takayuki Matsuo
- Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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22
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Abstract
PURPOSE OF REVIEW The purpose of this review is to examine the proposed role of immune modulation in the development and progression of diabetic kidney disease (DKD). RECENT FINDINGS Diabetic kidney disease has not historically been considered an immune-mediated disease; however, increasing evidence is emerging in support of an immune role in its pathophysiology. Both systemic and local renal inflammation have been associated with DKD. Infiltration of immune cells, predominantly macrophages, into the kidney has been reported in a number of both experimental and clinical studies. In addition, increased levels of circulating pro-inflammatory cytokines have been linked to disease progression. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease. Although no current therapies for DKD are directly based on immune modulation many of the therapies in clinical use have anti-inflammatory effects along with their primary actions. Macrophages emerge as the most likely beneficial immune cell target and compounds which reduce macrophage infiltration to the kidney have shown potential in both animal models and clinical trials.
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Affiliation(s)
- Fionnuala B Hickey
- Department of Clinical Medicine, Trinity College Dublin, Tallaght Hospital, Dublin, Dublin 24, Ireland
| | - Finian Martin
- School of Biomolecular & Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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Alicic RZ, Johnson EJ, Tuttle KR. Inflammatory Mechanisms as New Biomarkers and Therapeutic Targets for Diabetic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:181-191. [PMID: 29580582 DOI: 10.1053/j.ackd.2017.12.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/08/2023]
Abstract
Diabetic kidney disease (DKD) is the leading cause of CKD and end-stage kidney disease (ESKD) worldwide. Approximately 30-40% of people with diabetes develop this microvascular complication, placing them at high risk of losing kidney function as well as of cardiovascular events, infections, and death. Current therapies are ineffective for arresting kidney disease progression and mitigating risks of comorbidities and death among patients with DKD. As the global count of people with diabetes will soon exceed 400 million, the need for effective and safe treatment options for complications such as DKD becomes ever more urgent. Recently, the understanding of DKD pathogenesis has evolved to recognize inflammation as a major underlying mechanism of kidney damage. In turn, inflammatory mediators have emerged as potential biomarkers and therapeutic targets for DKD. Phase 2 clinical trials testing inhibitors of monocyte-chemotactic protein-1 chemokine C-C motif-ligand 2 and the Janus kinase/signal transducer and activator of transcription pathway, in particular, have produced promising results.
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Yu J, Wu H, Liu ZY, Zhu Q, Shan C, Zhang KQ. Advanced glycation end products induce the apoptosis of and inflammation in mouse podocytes through CXCL9-mediated JAK2/STAT3 pathway activation. Int J Mol Med 2017; 40:1185-1193. [PMID: 28849106 PMCID: PMC5593472 DOI: 10.3892/ijmm.2017.3098] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 08/09/2017] [Indexed: 01/11/2023] Open
Abstract
Diabetic nephropathy (DN) is a serious and one of the most common microvascular complications of diabetes. There is accumulating evidence to indicate that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under conditions of diabetes, play a role in DN. In this study, we found that the serum and urine levels of C-X-C motif chemokine ligand 9 (CXCL9) were significantly elevated in patients with DN compared with healthy controls. Based on an in vitro model of mouse podocyte injury, AGEs decreased the proliferation of podocytes and increased the expression of CXCL9 and C-X-C motif chemokine receptor 3 (CXCR3), and promoted the activation of signal transducer and activator of transcription 3 (STAT3). The knockdown of CXCL9 by the transfection of mouse podoyctes with specific siRNA significantly increased the proliferation and decreased the apoptosis of the podoyctes. Moreover, the levels of inflammatory factors, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 were also decreased in the podoyctes transfected with siRNA-CXCL9, accompanied by the increased expression of nephrin and podocin, and decreased levels of Bax/Bcl-2 and activated caspase-3. The knockdown of CXCL9 also led to the inactivation of the Janus kinase 2 (JAK2)/STAT3 pathway. Importantly, the use of the JAK2 inhibitor, AG490, and valsartan (angiotensin II receptor antagonist) attenuated the injury induced to mouse podoyctes by AGEs. On the whole, and to the best of our knowledge, this study demonstrates for the first time that AGEs exert pro-apoptotic and pro-inflammatory effects in mouse podoyctes through the CXCL9-mediated activation of the JAK2/STAT3 pathway. Thus, our data provide a potential therapeutic target for DN.
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Affiliation(s)
- Jing Yu
- Department of Endocrinology of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Hao Wu
- Department of Emergency Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Zi-Yu Liu
- Department of Endocrinology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Qi Zhu
- Department of Endocrinology of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Chang Shan
- Department of Endocrinology of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Ke-Qin Zhang
- Department of Endocrinology of Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
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Campion CG, Sanchez-Ferras O, Batchu SN. Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy. Can J Kidney Health Dis 2017; 4:2054358117705371. [PMID: 28616250 PMCID: PMC5461910 DOI: 10.1177/2054358117705371] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 02/17/2017] [Indexed: 12/11/2022] Open
Abstract
PURPOSE OF REVIEW Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. OBJECTIVE In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. METHODS We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. KEY FINDINGS In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. LIMITATIONS Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. IMPLICATIONS Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.
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Affiliation(s)
- Carole G. Campion
- Centre de recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM), Québec, Canada
| | - Oraly Sanchez-Ferras
- Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Québec, Canada
| | - Sri N. Batchu
- St. Michael’s Hospital, University of Toronto, Ontario, Canada
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Mohabbulla Mohib M, Fazla Rabby S, Paran TZ, Mehedee Hasan M, Ahmed I, Hasan N, Abu Taher Sagor M, Mohiuddin S. Protective role of green tea on diabetic nephropathy—A review. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/23312025.2016.1248166] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Md. Mohabbulla Mohib
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - S.M. Fazla Rabby
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Tasfiq Zaman Paran
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md. Mehedee Hasan
- Department of Pharmacy, State University of Bangladesh, Dhaka 1205, Bangladesh
| | - Iqbal Ahmed
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Nahid Hasan
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Md. Abu Taher Sagor
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Sarif Mohiuddin
- Department of Anatomy, Pioneer Dental College and Hospital, Dhaka 1229, Bangladesh
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Baquedano E, Burgos-Ramos E, Canelles S, González-Rodríguez A, Chowen JA, Argente J, Barrios V, Valverde AM, Frago LM. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model. Dis Model Mech 2016; 9:573-83. [PMID: 27013528 PMCID: PMC4892662 DOI: 10.1242/dmm.023515] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 03/11/2016] [Indexed: 01/12/2023] Open
Abstract
Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus.
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Affiliation(s)
- Eva Baquedano
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Emma Burgos-Ramos
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Sandra Canelles
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Agueda González-Rodríguez
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid E-28029, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Julie A Chowen
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Jesús Argente
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Vicente Barrios
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Angela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid E-28029, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid E-28029, Spain
| | - Laura M Frago
- Department of Paediatrics, Universidad Autónoma de Madrid, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid 28009, Spain Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid E-28006, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28029, Spain
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Elsherbiny NM, Al-Gayyar MMH. The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 2016; 81:15-22. [PMID: 26836949 DOI: 10.1016/j.cyto.2016.01.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 01/24/2016] [Indexed: 12/18/2022]
Abstract
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Nehal M Elsherbiny
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
| | - Mohammed M H Al-Gayyar
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
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29
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Barutta F, Bruno G, Grimaldi S, Gruden G. Inflammation in diabetic nephropathy: moving toward clinical biomarkers and targets for treatment. Endocrine 2015; 48:730-42. [PMID: 25273317 DOI: 10.1007/s12020-014-0437-1] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 09/21/2014] [Indexed: 12/13/2022]
Abstract
Diabetic nephropathy (DN) is a leading cause of end stage renal failure and there is an urgent need to identify new clinical biomarkers and targets for treatment to effectively prevent and slow the progression of the complication. Many lines of evidence show that inflammation is a cardinal pathogenetic mechanism in DN. Studies in animal models of experimental diabetes have demonstrated that there is a low-grade inflammation in the diabetic kidney. Both pharmacological and genetic strategies targeting inflammatory molecules have been shown to be beneficial in experimental DN. In vitro studies have cast light on the cellular mechanisms whereby diabetes triggers inflammation and in turn inflammation magnifies the kidney injury. Translation of this basic science knowledge into potential practical clinical applications is matter of great interest for researchers today. This review focuses on key pro-inflammatory systems implicated in the development of DN: the tumor necrosis factor(TNF)-α/TNF-α receptor system, the monocyte chemoattractant protein-1/CC-chemokine receptor-2 system, and the Endocannabinoid system that have been selected as they appear particularly promising for future clinical applications.
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Affiliation(s)
- Federica Barutta
- Department of Medical Sciences, University of Turin, C/so AM Dogliotti 14, Turin, Italy
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30
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Donate-Correa J, Martín-Núñez E, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res 2015; 2015:948417. [PMID: 25785280 PMCID: PMC4345080 DOI: 10.1155/2015/948417] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/17/2015] [Accepted: 01/31/2015] [Indexed: 12/12/2022] Open
Abstract
Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- *Javier Donate-Correa: and
| | - Ernesto Martín-Núñez
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Mercedes Muros-de-Fuentes
- Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Juan F. Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Nephrology Service, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- *Juan F. Navarro-González:
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31
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Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules 2014; 19:12727-59. [PMID: 25140450 PMCID: PMC6271622 DOI: 10.3390/molecules190812727] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 08/06/2014] [Accepted: 08/12/2014] [Indexed: 12/16/2022] Open
Abstract
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis.
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Affiliation(s)
- Bo-hyun Choi
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420-743, Korea.
| | - Kyung-Shin Kang
- Daewon Foreign Language High School, Kwangjin-gu, Seoul 143-713, Korea.
| | - Mi-Kyoung Kwak
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420-743, Korea.
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García-García PM, Getino-Melián MA, Domínguez-Pimentel V, Navarro-González JF. Inflammation in diabetic kidney disease. World J Diabetes 2014; 5:431-443. [PMID: 25126391 PMCID: PMC4127580 DOI: 10.4239/wjd.v5.i4.431] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 02/24/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.
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Elseweidy MM, Elswefy SE, Ali AE, Shawky M. Renal injury induced in alloxan diabetic rats. Role of Mycophenolate Mofetil as therapeutic agent. Pathol Res Pract 2014; 210:979-84. [PMID: 24939145 DOI: 10.1016/j.prp.2014.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 04/27/2014] [Accepted: 05/12/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND Renal injury may develop in uncontrolled chronic hyperglycemia due to increased oxidative stress and release of pro-inflammatory mediators, leading to diabetic complications. METHODS Mycophenolate Mofetil (MMF) is an immunosuppressant drug, an inhibitor of inosine monophosphate dehydrogenase (IMPDH), relevant to inflammation processes. MMF effect was tested in alloxan-diabetic rats on selected parameters like oxidative stress, gene expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1), in relation to microalbuminuria and renal function. RESULTS We found that the onset of microalbuminuria preceded the increase in serum glucose after alloxan treatment. Gene expression of TNF-α and TGF-β1 showed gradual increase after one and two weeks of alloxan administration as compared to the normal group. MMF administration decreased the gene expression of TNF-α and TGF-β1 in kidney tissues, serum glucose, fructosamine, urea, creatinine, C-reactive protein, malondialdehyde, urinary microalbumin and total protein. Histological examination of kidney tissues showed significant improvement in MMF treated rats as compared to diabetic control. CONCLUSIONS MMF modulated renal injury of alloxan diabetic rats. Collective data may support its therapeutic effect but further clinical trials may be requested.
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Affiliation(s)
- Mohamed M Elseweidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Sahar E Elswefy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Abd Elmoniem Ali
- Pathology Department, Faculty of Veterinary Medicine, Zagazig University, Egypt
| | - Mohamed Shawky
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; Biochemistry Department, Faculty of Pharmacy, Delta University, Dakahlia, Egypt.
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Ahad A, Ganai AA, Mujeeb M, Siddiqui WA. Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats. Toxicol Appl Pharmacol 2014; 279:1-7. [PMID: 24848621 DOI: 10.1016/j.taap.2014.05.007] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/05/2014] [Accepted: 05/12/2014] [Indexed: 12/23/2022]
Abstract
Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-кB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-β), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway.
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Affiliation(s)
- Amjid Ahad
- Lipid Metabolism Laboratory, Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ajaz Ahmad Ganai
- Department of Biotechnology, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Mohd Mujeeb
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Waseem Ahmad Siddiqui
- Lipid Metabolism Laboratory, Department of Biochemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India.
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Xu XX, Qi XM, Zhang W, Zhang CQ, Wu XX, Wu YG, Wang K, Shen JJ. Effects of total glucosides of paeony on immune regulatory toll-like receptors TLR2 and 4 in the kidney from diabetic rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2014; 21:815-823. [PMID: 24462407 DOI: 10.1016/j.phymed.2013.12.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/21/2013] [Accepted: 12/20/2013] [Indexed: 06/03/2023]
Abstract
TLRs are a family of receptors that play a critical role in the pathogenesis of diabetic nephropathy. TGP have been shown to have anti-inflammatory and immuno-regulatory activities. However, the relation between TGP and TLRs on diabetic nephropathy remains unknown. In this study, we examined effects of TGP on immune regulatory TLR2 and 4 in the kidney from streptozotocin-induced diabetic rats. TGP decreased the levels of 24h urinary albumin excretion rate significantly in diabetic rats. Western blot analysis showed that TGP significantly inhibited the expression of TLR2 and 4, MyD88, p-IRAK1, NF-κB p65, p-IRF3, TNF-α and IL-1β. Quantitative real-time PCR analysis showed that the significantly increased levels of TLR2 and 4, and MyD88mRNA in the kidneys of diabetic rats were significantly suppressed by TGP treatment. Macrophages infiltration were also markedly increased in the kidneys of the diabetic rats, but were significantly inhibited by TGP in a dose-dependent manner. These results suggest that TGP has protective effects on several pharmacological targets in the progress of diabetic nephropathy by selectively blocking TLRs activation in vivo.
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Affiliation(s)
- Xing-xin Xu
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Xiang-Ming Qi
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Wei Zhang
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Chao-Qun Zhang
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Xiao-Xu Wu
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Yong-Gui Wu
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China.
| | - Kun Wang
- Department of Nephrology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, PR China
| | - Ji-Jia Shen
- Department of Pathobiology, Anhui Medical University, Hefei, Anhui, PR China
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Omote K, Gohda T, Murakoshi M, Sasaki Y, Kazuno S, Fujimura T, Ishizaka M, Sonoda Y, Tomino Y. Role of the TNF pathway in the progression of diabetic nephropathy in KK-A(y) mice. Am J Physiol Renal Physiol 2014; 306:F1335-47. [PMID: 24647715 DOI: 10.1152/ajprenal.00509.2013] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-α remains unclear. The objectives of the present study were to examine whether TNF-α inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-A(y) mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-α and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-α and TNFR1, in ETN-treated KK-A(y) mice were significantly decreased compared with untreated KK-A(y) mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-α or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-α-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-α-TNFR2 pathway.
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Affiliation(s)
- Keisuke Omote
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Maki Murakoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yu Sasaki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Saiko Kazuno
- Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Tsutomu Fujimura
- Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masanori Ishizaka
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yuji Sonoda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
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Elseweidy MM, Elswefy SE, Younis NN, Zaghloul MS. Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy. Exp Biol Med (Maywood) 2014; 238:881-8. [PMID: 23970406 DOI: 10.1177/1535370213494644] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the major complications that develop as consequence of chronic and uncontrolled hyperglycaemia. Hyperglycaemia initiates various processes, one of which is protein glycation, leading to the formation of advanced glycation end products. Alteration of intracellular signalling, gene expression, release of proinflammatory molecules and free radicals are examples of such changes and they contribute to the initiation of diabetic complications. In the current manuscript, we studied the effect of pyridoxamine (PM) on protein glycation, oxidative stress, interleukin-1α (IL-1α), IL-6, C-reactive protein (CRP), gene expression of tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in relation to microalbuminuria and kidney functions in a model of alloxan-induced diabetic rats. We have observed that onset of microalbuminuria has preceded the gradual increase of blood sugar level in diabetic rats. In diabetic rats, gene expression of TNF-α and TGF-β1 recorded a gradual increase and marked increase was observed after one and two weeks of alloxan administration, in comparison with normal rats. PM induced significant decrease in kidney malondialdehyde content and the gene expression of TNF-α and TGF-β1, in addition to levels of serum glucose, fructosamine, urea, creatinine, IL-1α, IL-6, CRP and urine microalbumin. Histopathological examination of kidney tissues showed certain improvements as compared with diabetic control. In conclusion, our results may provide a supporting evidence for the therapeutic benefit of PM in DN.
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Palomer X, Salvadó L, Barroso E, Vázquez-Carrera M. An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int J Cardiol 2013; 168:3160-72. [PMID: 23932046 DOI: 10.1016/j.ijcard.2013.07.150] [Citation(s) in RCA: 222] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 07/15/2013] [Indexed: 10/26/2022]
Abstract
Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-κB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-κB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy.
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Affiliation(s)
- Xavier Palomer
- Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain
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Hickey FB, Martin F. Diabetic kidney disease and immune modulation. Curr Opin Pharmacol 2013; 13:602-12. [DOI: 10.1016/j.coph.2013.05.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 04/23/2013] [Accepted: 05/03/2013] [Indexed: 12/11/2022]
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40
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Lv SS, Liu G, Wang JP, Wang WW, Cheng J, Sun AL, Liu HY, Nie HB, Su MR, Guan GJ. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. Int Immunopharmacol 2013; 17:275-82. [PMID: 23791972 DOI: 10.1016/j.intimp.2013.05.031] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 05/13/2013] [Accepted: 05/27/2013] [Indexed: 12/29/2022]
Abstract
Mesenchymal stem cells (MSCs) treatment has been shown to be effective in diabetic nephropathy (DN). However, the mechanisms involved in the renoprotective effects of MSCs have not been clearly demonstrated. Especially, there was no study on the relationship of MSCs and macrophages in diabetic kidney. To explore the effect of MSCs on macrophages in DN, streptozotocin-induced diabetes animals received no treatment or treatment with MSCs (2×10(6), via tail vein) for two continuous weeks. Eight weeks after treatment, physical, biochemical and morphological parameters were measured. Immunohistochemistry for fibronectin (FN), CollagenI, ED-1, monocyte chemoattractant protein-1 (MCP-1) was performed. Expressions of pro-inflammatory cytokines and hepatocyte growth factor (HGF) at gene level and protein level were determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Blood glucose, urinary albumin excretion, creatinine clearance were significantly reduced after MSCs treatment. The glomerulosclerosis as revealed by periodic acid Schiff stain and expression of FN and CollagenI was also dramatically attenuated. Most importantly, the expression of MCP-1 and the number of infiltrated macrophages in kidney were effectively suppressed by MSCs treatment. The expression of HGF in MSCs group was up-regulated. Meanwhile, the expressions of IL-1β, IL-6 and TNFα were significantly down-regulated by MSCs treatment. Our study suggest that MSCs treatment ameliorates DN via inhibition of MCP-1 expression by secreting HGF, thus reducing macrophages infiltration, down-regulating IL-1β, IL-6, TNFα expression in renal tissue in diabetic rats.
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Affiliation(s)
- Sha-Sha Lv
- Shandong University, Jinan, Shandong, China
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41
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Zhao J, Fan YC, Sun FK, Zhao ZH, Wang LY, Hu LH, Yin YP, Li T, Gao S, Wang K. Peripheral type I interferon receptor correlated with oxidative stress in chronic hepatitis B virus infection. J Interferon Cytokine Res 2013; 33:405-14. [PMID: 23663046 DOI: 10.1089/jir.2012.0153] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Type I interferon receptor (IFNAR) has been involved in the progression of chronic hepatitis B (CHB). Oxidative stress is also associated with hepatitis B virus (HBV) infection and might contribute to the structure and function of protein synthesis including the IFNAR family. This study was aimed to determine the possible associations between oxidative stress and peripheral IFNAR expression in chronic HBV infection. Fifty-four CHB patients and 31 liver cirrhosis (LC) patients were consecutively collected, as well as 11 healthy subjects as controls. Expression levels of IFNAR1 and IFNAR2 in peripheral blood lymphocytes and monocytes were measured by flow cytometry. IFNAR1 and IFNAR2c mRNA were detected by real-time reverse transcription-polymerase chain reaction. Levels of plasma-soluble IFNAR and oxidative stress parameters, including xanthine oxidase (XOD), malondialdehyde (MDA), glutathione (GSH), glutathione S-transferase (GST), and glutathione peroxidase (GSH-Px) were detected by enzyme linked immunosorbent assay (ELISA). The frequencies of IFNAR1 and IFNAR2 in lymphocytes and monocytes were significantly increased in CHB and LC patients than in healthy controls. Expression levels of IFNAR1 and IFNAR2c mRNA and plasma-soluble IFNAR level in CHB and LC patients were upregulated compared with healthy controls. Mean fluorescence intensity (MFI) of IFNAR2 in monocytes of CHB patients was higher than that in LC patients. Levels of plasma XOD, MDA, and GST were significantly increased in CHB and LC patients compared with healthy controls. Meanwhile, GSH and GSH-Px in CHB and LC patients were decreased than that in healthy controls. Furthermore, plasma MDA, GSH, and GST levels in CHB patients were higher than that in LC patients. In CHB patients, plasma GST level was negatively correlated with MFI of IFNAR2 in lymphocytes. Our results suggested that oxidative stress play an important role in the regulation of IFNAR in chronic HBV infection.
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Affiliation(s)
- Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
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Abstract
Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.
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Abstract
Diabetic nephropathy (DN), the most common cause of end-stage renal disease (ESRD), is increasingly considered an inflammatory process characterized by leukocyte infiltration at every stage of renal involvement. Cytokines act as pleiotropic polypeptides that regulate inflammatory and immune responses, providing important signals in the pathologic and physiologic processes. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Proinflammatory, Th1, Th2, and Th17 cytokines, as well as TGF-beta, all take part in the development and progression of DN. Gene polymorphism of cytokines and their receptors may have functional variations and can be applied to predict the susceptibility and progression to DN. Improved knowledge on recognizing cytokines as significant pathogenic mediators in DN leaves opens the possibility of new potential therapeutic agents for future clinical treatments.
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Affiliation(s)
- Chia-Chao Wu
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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44
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Zheng JM, Yao GH, Cheng Z, Wang R, Liu ZH. Pathogenic role of mast cells in the development of diabetic nephropathy: a study of patients at different stages of the disease. Diabetologia 2012; 55:801-11. [PMID: 22130579 DOI: 10.1007/s00125-011-2391-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 11/04/2011] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Increased renal mast cells have been detected in diabetic nephropathy. However, only a few patients have been examined. Evidence of the involvement of mast cells in diabetic nephropathy is still scarce, and no observation of mast cells during the development of diabetic nephropathy has yet been reported in humans. Here, we examined changes in renal mast cells in patients at different stages of diabetic nephropathy and related these to the development of the disease. METHODS Eighty patients at different clinical stages of diabetic nephropathy and 16 normal kidney donors were recruited. Immunohistochemical staining for tryptase, chymase, TGF-β1, renin and TNF-α was done on renal sections from patients and control participants. Changes in mast cell number, degranulation, subtype and phenotype were examined. Correlation between mast cells and patients' clinical and pathological indices was analysed. RESULTS With progression of diabetic nephropathy, the number and degranulation level of mast cells increased. Increase in mast cell number and degranulation level correlated significantly with tubular interstitial injury. Almost all renal mast cells in patients with diabetic nephropathy were found to produce chymase, renin, TGF-β1 and TNF-α. The level of TNF-α in mast cells increased with progression of diabetic nephropathy. CONCLUSIONS/INTERPRETATION This study suggests that mast cells are involved in development of diabetic nephropathy. Through release of bioactive substances, such as tryptase, chymase, TGF-β1, renin and TNF-α, into the tubular interstitium by degranulation, mast cells could promote renal inflammation and fibrosis, and thus contribute to diabetic nephropathy.
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Affiliation(s)
- J M Zheng
- Research Institute of Nephrology, Jingling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, People's Republic of China
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Wang H, Jiang YW, Zhang WJ, Xu SQ, Liu HL, Yang WY, Lou JN. Differential activations of PKC/PKA related to microvasculopathy in diabetic GK rats. Am J Physiol Endocrinol Metab 2012; 302:E173-82. [PMID: 21989030 DOI: 10.1152/ajpendo.00184.2011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Microvasculopathy is the most serious and predictable threat to the health of diabetic patients, which often results in end-stage renal disease, blindness, and limb amputations. Up to the present, the underlying mechanisms have remained elusive. Here, it was found that the differential activations of PKC/PKA were involved in diabetic microvasculopathy in diabetic GK rats. By real-time PCR, Western blot, immunohistochemistry, and enzyme activity assay, upregulation of PKC was prominent in kidney but was not significant in liver and brain. The expression and activity of PKA were lowered in kidney but comparable in brain and liver during diabetic nephropathy. Furthermore, the generation of reactive oxygen species, production of nitric oxide, and expression of inducible nitric oxide synthase induced by advanced glycation end products were inhibited by PKCβ inhibitor LY-333531 or a PKA agonist in rat glomerular microvascular endothelial cells. Finally, albuminuria was significantly lowered by a PKA agonist and boosted by a PKA antagonist. It suggested that the differential activations of PKC/PKA related to microvasculopathy in diabetes and that activation of PKA may protect the diabetic microvasculature.
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Affiliation(s)
- Hui Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
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46
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Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011; 7:327-40. [DOI: 10.1038/nrneph.2011.51] [Citation(s) in RCA: 797] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Zhang Q, Huang JH, Xia RP, Duan XH, Jiang YB, Jiang Q, Sun WJ. Suppression of Experimental Abdominal Aortic Aneurysm in a Rat Model by the Phosphodiesterase 3 Inhibitor Cilostazol. J Surg Res 2011; 167:e385-93. [DOI: 10.1016/j.jss.2011.01.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 12/16/2010] [Accepted: 01/11/2011] [Indexed: 11/26/2022]
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Shankaran H, Chrisler WB, Sontag RL, Weber TJ. Inhibition of ERK oscillations by ionizing radiation and reactive oxygen species. Mol Carcinog 2010; 50:424-32. [PMID: 21557328 DOI: 10.1002/mc.20724] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 11/01/2010] [Accepted: 11/19/2010] [Indexed: 01/12/2023]
Abstract
The shuttling of activated protein kinases between the cytoplasm and nucleus is an essential feature of normal growth factor signaling cascades. Here we demonstrate that transforming growth factor alpha (TGFα) induces oscillations in extracellular signal regulated kinase (ERK) cytoplasmic-nuclear translocations in human keratinocytes. TGFα-dependent ERK oscillations mediated through the epidermal growth factor receptor (EGFR) are inhibited by low dose X-irradiation (10 cGy) and low concentrations of hydrogen peroxide (0.32-3.26 µM H(2)O(2)) used as a model reactive oxygen species (ROS). A fluorescent indicator dye (H2-DCFDA) was used to measure cellular ROS levels following X-irradiation, 12-O-tetradecanoyl phorbol-13-acetate (TPA) and H(2)O(2). X-irradiation did not generate significant ROS production while 0.32 µM H(2)O(2) and TPA induced significant increases in ROS levels with H(2)O(2) > TPA. TPA alone induced transactivation of the EGFR but did not induce ERK oscillations. TPA as a cotreatment did not inhibit TGFα-stimulated ERK oscillations but qualitatively altered TGFα-dependent ERK oscillation characteristics (amplitude, time-period). Collectively, these observations demonstrate that TGFα-induced ERK oscillations are inhibited by ionizing radiation/ROS and perturbed by epigenetic carcinogen in human keratinocytes.
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Affiliation(s)
- Harish Shankaran
- Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington 99354, USA
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49
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Vasculoprotective effect of cilostazol in aldosterone-induced hypertensive rats. Hypertens Res 2009; 33:229-35. [PMID: 20019701 DOI: 10.1038/hr.2009.211] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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50
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Muriel P. Role of free radicals in liver diseases. Hepatol Int 2009; 3:526-36. [PMID: 19941170 DOI: 10.1007/s12072-009-9158-6] [Citation(s) in RCA: 258] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 09/23/2009] [Accepted: 11/11/2009] [Indexed: 12/16/2022]
Abstract
Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B(1) consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.
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Affiliation(s)
- Pablo Muriel
- Department of Pharmacology, Cinvestav-I.P.N., Apdo. Postal 14-740, Mexico, 07000 D.F. Mexico
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