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Chowdhury A, Mitra Mazumder P. Unlocking the potential of flavonoid-infused drug delivery systems for diabetic wound healing with a mechanistic exploration. Inflammopharmacology 2024:10.1007/s10787-024-01561-5. [PMID: 39217278 DOI: 10.1007/s10787-024-01561-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024]
Abstract
Diabetes is one of the common endocrine disorders generally characterized by elevated levels of blood sugar. It can originate either from the inability of the pancreas to synthesize insulin, which is considered as an autoimmune disorder, or the reduced production of insulin, considered as insulin resistivity. A wound can be defined as a condition of damage to living tissues including skin, mucous membrane and other organs as well. Wounds get complicated with respect to time based on specific processes like diabetes mellitus, obesity and immunocompromised conditions. Proper growth and functionality of the epidermis gets sustained due to impaired diabetic wound healing which shows a sign of dysregulated wound healing process. In comparison with synthetic medications, phytochemicals like flavonoids, tannins, alkaloids and glycosides have gained enormous importance relying on their distinct potential to heal diabetic wounds. Flavonoids are one of the most promising and important groups of natural compounds which can be used to treat acute as well as chronic wounds. Flavonoids show excellent properties due to the presence of hydroxyl groups in their chemical structure, which makes this class of compounds different from others. Based on the novel principles of nanotechnology via utilizing suitable drug delivery systems, the delivery of bioactive constituents from plant source amplifies the wound-healing mechanism, minimizes complexities and enhances bioavailability. Hence, the encapsulation and applicability of flavonoids with an emphasis on mechanistic route and wound-healing therapeutics have been highlighted in the subsequent study with focus on multiple drug delivery systems.
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Affiliation(s)
- Ankit Chowdhury
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India
| | - Papiya Mitra Mazumder
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
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Sun C, Huang Y, Wang L, Deng J, Qing R, Ge X, Han X, Zha G, Pu W, Wang B, Hao S. Engineered keratin/bFGF hydrogel to promote diabetic wound healing in rats. Int J Biol Macromol 2024; 261:129725. [PMID: 38272410 DOI: 10.1016/j.ijbiomac.2024.129725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Keratin materials are promising in wound healing acceleration, however, it is a challenge for the keratin to efficiently therapy the impaired wound healing, such as diabetic foot ulcers. Here, we report a keratin/bFGF hydrogel for skin repair of chronic wounds in diabetic rats based on their characteristics of extracellular matrix and growth factor degradation in diabetic ulcer. Recombinant keratin 31 (K31), the most abundant keratin in human hair, exhibited the highly efficient performances in cell adhesion, proliferation and migration. More importantly, the introduction of bFGF into K31 hydrogel significantly enhances the properties of cell proliferation, wound closure acceleration, angiogenesis and skin appendages regeneration. Furthermore, the combination of K31 and bFGF can promote epithelial-mesenchymal transition by inhibiting the expression of E-cadherin and promoting the expression of vimentin and fibronectin. These findings demonstrate the engineered K31/bFGF hydrogel as a promising therapeutic agent for diabetic wound healing.
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Affiliation(s)
- Changfa Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Yuqian Huang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Lili Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Jia Deng
- College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China
| | - Rui Qing
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xin Ge
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Xue Han
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Guodong Zha
- HEMOS (Chongqing) Bioscience Co., Ltd, Chongqing 402760, China
| | - Wei Pu
- School of Aeronautics and Astronautics, Sichuan University, Chengdu 610065, China.
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
| | - Shilei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
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Zhu C, Li S. The peripheral corticotropin releasing factor family's role in vasculitis. Vascul Pharmacol 2024; 154:107275. [PMID: 38184094 DOI: 10.1016/j.vph.2023.107275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/15/2023] [Accepted: 12/31/2023] [Indexed: 01/08/2024]
Abstract
Corticotropin releasing factor family peptides (CRF peptides) include 4 members, corticotropin releasing hormone (CRH), Urocortin (UCN1), UCN2 and UCN3. CRF peptides function via the two distinct receptors, CRF1 and CRF2. Among them, CRH/CRF1 has been recognized to influence immunity/inflammation peripherally. Both pro- and anti-inflammatory effects of CRH are reported. Likewise, UCNs, peripherally in cardiovascular system have been documented to have both potent protective and harmful effects, with UCN1 acting on both CRF1 & CRF2 and UCN2 & UCN3 on CRF2. We and others also observe protective and detrimental effects of CRF peptides/receptors on vasculature, with the latter of predominantly higher incidence, i.e., they play an important role in the development of vasculitis while in some cases they are found to counteract vascular inflammation. The pro-vasculitis effects of CRH & UCNs include increasing vascular endothelial permeability, interrupting endothelial adherens & tight junctions leading to hyperpermeability, stimulating immune/inflammatory cells to release inflammatory factors, and promoting angiogenesis by VEGF release while the anti-vasculitis effects may be just the opposite, depending on many factors such as different CRF receptor types, species and systemic conditions. Furthermore, CRF peptides' pro-vasculitis effects are found to be likely related to cPLA2 and S1P receptor signal pathway. This minireview will focus on summarizing the peripheral effects of CRF peptides on vasculature participating in the processes of vasculitis.
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Affiliation(s)
- Chao Zhu
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue, 101, Nanjing, China
| | - Shengnan Li
- Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Longmian Avenue, 101, Nanjing, China.
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An L, Ren X, Pan Y, Gao W, Ren L, Wang J, Wang Y. IFN-γ, SCF, MIP1b and IL-16 Were Associated with Risk of Diabetic Nephropathy: A Mendelian Randomization Study. Diabetes Metab Syndr Obes 2024; 17:851-856. [PMID: 38410634 PMCID: PMC10895979 DOI: 10.2147/dmso.s452227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/03/2024] [Indexed: 02/28/2024] Open
Abstract
Background The impact of inflammatory factors on the risk of diabetic nephropathy (DN) is inconsistent. Two-sample Mendelian randomization (MR) analyses were used to detect the causal role of inflammatory factors in DN risk. Methods Inflammatory factor GWAS summary data were collected from a meta-analysis including 8,293 Finnish participants, and DN information was extracted from a GWAS of 213,746 individuals from FinnGen. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) outlier test was used for the removal of horizontal pleiotropic outliers. Multivariable MR analysis was also used to adjust for pleiotropy. Results IFN-γ [ORIVW: 1.33; 95% CI: 1.09-1.63; p=0.005] and SCF [ORIVW: 1.25, 1.02-1.52; p = 0.027] were associated with an increased risk of DN. MIP1b [ORIVW: 0.92; 95% CI: 0.85-0.98; p = 0.022] and IL-16 [ORIVW: 0.89, 0.81-0.99; p = 0.043] showed negative associations with the risk of DN. We validated our MR results with MR-PRESSO analyses. Significant horizontal pleiotropy was not found. Moreover, in the multivariable MR analysis, the associations between cytokines and DN risk remained. Conclusion Our MR results based on genetic data contribute to a better understanding of the pathogenesis of DN and provide evidence for a causal effect of inflammatory factors on DN. These findings support targeting specific inflammatory factors to alleviate DN risk.
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Affiliation(s)
- Li An
- Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
- Department of Endocrine, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
| | - Xiaomei Ren
- Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
| | - Ye Pan
- Department of Endocrine, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
| | - Wei Gao
- Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
| | - Liqun Ren
- Department of Geriatrics, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
| | - Jing Wang
- Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng, 211400, People’s Republic of China
| | - Yao Wang
- Department of Endocrine, ZhongDa Hospital, Southeast University School of Medicine, Nanjing, 210009, People’s Republic of China
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Wang X, Li R, Zhao H. Enhancing angiogenesis: Innovative drug delivery systems to facilitate diabetic wound healing. Biomed Pharmacother 2024; 170:116035. [PMID: 38113622 DOI: 10.1016/j.biopha.2023.116035] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/07/2023] [Accepted: 12/14/2023] [Indexed: 12/21/2023] Open
Abstract
Diabetic wounds (DW) constitute a substantial burden on global healthcare owing to their widespread occurrence as a complication of diabetes. Angiogenesis, a crucial process, plays a pivotal role in tissue recovery by supplying essential oxygen and nutrients to the injury site. Unfortunately, in diabetes mellitus, various factors disrupt angiogenesis, hindering wound healing. While biomaterials designed to enhance angiogenesis hold promise for the treatment of DWs, there is an urgent need for more in-depth investigations to fully unlock their potential in clinical management. In this review, we explore the intricate mechanisms of angiogenesis that are crucial for DW recovery. We introduce a rational design for angiogenesis-enhancing drug delivery systems (DDS) and provide a comprehensive summary and discussion of diverse biomaterials that enhance angiogenesis for facilitating DW healing. Lastly, we address emerging challenges and prospects in angiogenesis-enhancing DDS for facilitating DW healing, aiming to offer a comprehensive understanding of this critical healthcare issue and potential solutions.
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Affiliation(s)
- Xuan Wang
- Department of foot and ankle surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an 710054, China
| | - Runmin Li
- Department of foot and ankle surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an 710054, China
| | - Hongmou Zhao
- Department of foot and ankle surgery, Honghui Hospital of Xi'an Jiaotong University, Xi'an 710054, China.
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Altıncık SA, Yıldırımçakar D, Avcı E, Özhan B, Girişgen İ, Yüksel S. Plasma leucine-rich α-2-glycoprotein 1 - a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus? Pediatr Nephrol 2023; 38:4043-4049. [PMID: 37401956 DOI: 10.1007/s00467-023-06019-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/08/2023] [Accepted: 05/02/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Glomerular endothelial dysfunction and neoangiogenesis play a significant role in the pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a recently discovered protein that participates in the molecular pathway of inflammation and angiogenesis. We aimed to investigate efficacy of LRG1 to predict estimated glomerular filtration rate (eGFR) decrease in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS The study comprised 72 participants with diabetes duration for ≥ 2 years. At study initiation, LRG1, urine albumin, eGFR (cystatin C-based, and Schwartz), HbA1c, and lipid values were evaluated and diabetes-related clinical features and anthropometric measurements were collected. These results were compared with final control values after ≥ 1 year. Patients were divided into subgroups according to presence of albuminuria progression, eGFR decrease, and metabolic control parameters. RESULTS There was positive correlation between LRG1 level and Schwartz and cystatin C-based eGFR decline (r = 0.360, p = 0.003; r = 0.447, p = 0.001, respectively), and negative correlation between final cystatin C-based eGFR and LRG1 (p = 0.01, r = -0.345). Patients with cystatin C-based eGFR decrease > 10% had significantly higher LRG1 levels (p = 0.03), however, LRG1 was not different between albuminuria progression subgroups. A 0.282 μg/ml increase in LRG1 correlated with a 1% decrease in eGFR in simple linear regression analysis (β = 0.282, %CI 0.11-0.45, p = 0.001) and LRG1 was an independent predictor of GFR decline even in the presence of covariates. CONCLUSIONS Our study supports the relationship between plasma LRG1 and eGFR decline and suggests LRG1 may be an early marker of DKD progression in children with T1DM. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Selda Ayça Altıncık
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey
| | - Didem Yıldırımçakar
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey.
| | - Esin Avcı
- Department of Medical Biochemistry, Pamukkale University, Denizli, Turkey
| | - Bayram Özhan
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey
| | - İlknur Girişgen
- Department of Pediatric Nephrology, Pamukkale University, Denizli, Turkey
| | - Selçuk Yüksel
- Department of Pediatric Nephrology and Pediatric Rheumatology, Pamukkale University, Denizli, Turkey
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Hu HC, Lei YH, Zhang WH, Luo XQ. Antioxidant and Anti-inflammatory Properties of Resveratrol in Diabetic Nephropathy: A Systematic Review and Meta-analysis of Animal Studies. Front Pharmacol 2022; 13:841818. [PMID: 35355720 PMCID: PMC8959544 DOI: 10.3389/fphar.2022.841818] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/18/2022] [Indexed: 12/25/2022] Open
Abstract
Background: Accumulated experimental evidence suggests that resveratrol may have an effect on diabetic nephropathy by inhibiting inflammation and decreasing oxidative stress. However, the credibility of the evidence for this practice is unclear. Thus, we aimed to perform a systematic review and meta-analysis of animal studies to evaluate the antioxidant and anti-inflammatory properties of resveratrol when used in the treatment of diabetic nephropathy. Methods: Electronic bibliographic databases including PubMed, EMBASE, and Web of Science were searched for relevant studies. The methodological quality of animal studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Risk of Bias (SYRCLE’s RoB) tool. A meta-analysis was performed based on the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.4 software. This study was registered within International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42021293784. Results: Thirty-six qualified studies involving 726 animals were included. There was a significant association of resveratrol with the levels of blood glucose (BG), serum creatinine (Scr), blood urea nitrogen (BUN), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and interleukin-1β (IL-1β). Nevertheless, resveratrol treatment did not effectively decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, more remarkable antioxidant and hypoglycemic effects were observed in type 2 diabetic nephropathy rather than in type 1 diabetic nephropathy based on subgroup analysis. Conclusion: In this meta-analysis, resveratrol can exert its antioxidant activities by reducing the levels of MDA and recovering the activities of SOD, CAT, GSH, and GPx. With regard to pro-inflammatory cytokines, resveratrol had a positive effect on the reduction of IL-1β. However, the analysis indicated that resveratrol had no effect on IL-6 and TNF-α levels, probably because of the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory properties of resveratrol, but its relationship with the levels of some inflammatory cytokines such as IL-6 and TNF-α in animals with diabetic nephropathy needs further elucidation.
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Affiliation(s)
- Heng-Chang Hu
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan-Hong Lei
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei-Hua Zhang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao-Qiong Luo
- Department of Neurology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
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Pannangpetch P, Thongrung R, Senggunprai L, Hipkaeo W, Tangsucharit P. Anti-angiogenesis and anti-inflammatory effects of Moringa oleifera leaf extract in the early stages of streptozotocin-induced diabetic nephropathy in rats. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.350177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Salem M, Sallam AAM, Abdel-Aleem E, El-Mesallamy HO. Effect of Lisinopril and Verapamil on Angiopoietin 2 and Endostatin in Hypertensive Diabetic Patients with Nephropathy: A Randomized Trial. Horm Metab Res 2021; 53:470-477. [PMID: 34282598 DOI: 10.1055/a-1517-6643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Angiogenesis is a multistep process implicated in the pathophysiology and progression of diabetic nephropathy (DN). Angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have an important role in DN. We performed a randomized-controlled trial of lisinopril alone (an ACEI) or in combination with verapamil (a CCB) as a therapy for DN in type 2 diabetes mellitus (T2DM) patients with hypertension (HTN) and urinary albumin creatinine ratio (UACR) (30-300 mg/g) also to evaluate their effect on UACR, the angiogenic proteins: Angiopoietin 2 (Ang-2) and Endostatin (EST). Forty T2DM patients with microalbuminuria, aged 45-65 years were included. Patients were randomly assigned into group 1 receiving oral lisinopril and group 2 receiving oral lisinopril and verapamil once daily. After 3 months follow-up fasting blood glucose (FPG), HbA1c, lipid profile, UACR, serum urea and creatinine levels were assessed. EST and Ang-2 were measured using ELISA technique. Baseline Ang-2 and EST levels were elevated in both groups compared with controls (p<0.001). After follow-up, group 2 had significantly decreased FPG, HbA1c, UACR, EST and Ang-2 compared with their baseline levels (p<0.001 for all comparisons) and with group 1 (p<0.001). No adverse reactions were reported. Baseline EST and Ang-2 were positively correlated to UACR (r=0.753, p<0.001) (r=0.685, p<0.001). Lisinopril/verapamil combination enhanced glycemic control and kidney function via diminishing EST and Ang-2. This combination can be considered as a safe and effective approach for early stage nephropathy therapy in T2DM.
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Affiliation(s)
- Mohamed Salem
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Biochemistry Department, Badr University in Cairo (BUC), Badr City, Cairo, Egypt
| | - Eman Abdel-Aleem
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Hala O El-Mesallamy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Sinai University, Kantara Branch, Cairo, Egypt
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Liu Y, Chen D, Smith A, Ye Q, Gao Y, Zhang W. Three-dimensional remodeling of functional cerebrovascular architecture and gliovascular unit in leptin receptor-deficient mice. J Cereb Blood Flow Metab 2021; 41:1547-1562. [PMID: 33818188 PMCID: PMC8221780 DOI: 10.1177/0271678x211006596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/17/2022]
Abstract
The cerebrovascular sequelae of diabetes render victims more susceptible to ischemic stroke, vascular cognitive impairment, and Alzheimer's disease. However, limited knowledge exists on the progressive changes in cerebrovascular structure and functional remodeling in type 2 diabetes. To ascertain the impact of diabetes on whole-brain cerebrovascular perfusion, leptin-receptor-deficient mice were transcardially injected with tomato-lectin before sacrifice. The whole brain was clarified by the Fast free-of-acrylamide clearing tissue technique. Functional vascular anatomy of the cerebrum was visualized by light-sheet microscopy, followed by analysis in Imaris software. We observed enhanced neovascularization in adult db/db mice, characterized by increased branch level and loop structures. Microvascular hypoperfusion was initially detected in juvenile db/db mice, suggesting early onset of insufficient microcirculation. Furthermore, gliovascular unit remodeling was verified by loss of pericytes and overactivation of microglia and astrocytes in adult diabetic mice. However, the integrity of the blood-brain barrier (BBB) was fundamentally preserved, as shown by a lack of extravasation of IgG into the brain parenchyma. In summary, we, for the first time, reveal that functional cerebrovascular remodeling occurs as early as four weeks in db/db mice and the deficit in gliovascular coupling may play a role in cerebral hypoperfusion before BBB breakdown in 16-week-old db/db mice.
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Affiliation(s)
- Yaan Liu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Di Chen
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Amanda Smith
- Department of Neurology, Pittsburgh Institute of Brain Disorders & Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Qing Ye
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Yanqin Gao
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Wenting Zhang
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA
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Wang L, Wang P, Li X, Dong Y, Wu S, Xu M, Chen X, Wang S, Zheng C, Zou C. Combination CTLA-4 immunoglobulin treatment and ultrasound microbubble-mediated exposure improve renal function in a rat model of diabetic nephropathy. Aging (Albany NY) 2021; 13:8524-8540. [PMID: 33714204 PMCID: PMC8034886 DOI: 10.18632/aging.202664] [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: 06/16/2020] [Accepted: 02/01/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVE This study explored the therapeutic impact of combined cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) treatment and microbubble-mediated exposure in a rat model of diabetic nephropathy (DN). METHOD We treated rats using CTLA-4-Ig and/or microbubble exposure. At 8 weeks post-intervention, key parameters were evaluated including blood biochemistry, damage to renal tissue, renal parenchymal elasticity, ultrastructural changes in podocytes, and renal parenchymal expression of CD31, CD34, IL-6, Fn, Collagen I, Talin, Paxillin, α3β1, podocin, nephrin, and B7-1. RESULT We found that renal function in the rat model of DN can be significantly improved by CTLA-4-Ig and CTLA-4-Ig + ultrasound microbubble treatment. Treatment efficacy was associated with reductions in renal parenchymal hardness, decreases in podocyte reduction, decreased IL-6, Fn and Collagen I expression, increased Talin, Paxillin and α3β1 expression, elevated podocin and nephrin expression, and decreased B7-1 expression. In contrast, these treatments did not impact CD31 or CD34 expression within the renal parenchyma. CONCLUSION These findings clearly emphasize that CTLA-4-Ig can effectively prevent podocyte damage, inhibiting inflammation and fibrosis, and thereby treating and preventing DN. In addition, ultrasound microbubble exposure can improve the ability of CTLA-4-Ig to pass through the glomerular basement membrane in order to access podocytes such that combination CTLA-4-Ig + microbubble exposure treatment is superior to treatment with CTLA-4-Ig only.
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Affiliation(s)
- Liang Wang
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Pengfei Wang
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Xiuyun Li
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Yanyan Dong
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Senmin Wu
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Maosheng Xu
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Xiu Chen
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Shijia Wang
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
| | - Chao Zheng
- Department of Endocrinology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China
| | - Chunpeng Zou
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
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Alomari G, Hamdan S, Al-Trad B. Gold nanoparticles as a promising treatment for diabetes and its complications: Current and future potentials. BRAZ J PHARM SCI 2021. [DOI: 10.1590/s2175-97902020000419040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Ghada Alomari
- Universiti Teknologi Malaysia, Malaysia; Yarmouk University, Jordan
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Alomari G, Al-Trad B, Hamdan S, Aljabali A, Al-Zoubi M, Bataineh N, Qar J, Tambuwala MM. Gold nanoparticles attenuate albuminuria by inhibiting podocyte injury in a rat model of diabetic nephropathy. Drug Deliv Transl Res 2020; 10:216-226. [PMID: 31637677 PMCID: PMC6978433 DOI: 10.1007/s13346-019-00675-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Several recent studies have reported that gold nanoparticles (AuNPs) attenuate hyperglycemia in diabetic animal models without any observed side effects. The present study was intended to provide insight into the effects of 50-nm AuNPs on diabetic kidney disease. Adult male rats were divided into three groups (n = 7/group): control (non-diabetic, ND), diabetic (D), and diabetic treated intraperitoneally with 50-nm AuNPs (AuNPs + D; 2.5 mg/kg/day) for 7 weeks. Diabetes was induced by a single-dose injection of 55 mg/kg streptozotocin. The result showed that AuNP treatment prevented diabetes-associated increases in the blood glucose level. Reduction in 24-h urinary albumin excretion rate, glomerular basement membrane thickness, foot process width, and renal oxidative stress markers was also demonstrated in the AuNP-treated group. In addition, the results showed downregulation effect of AuNPs in renal mRNA or protein expression of transforming growth factor β1 (TGF-β1), fibronectin, collagen IV, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor-A (VEGF-A). Moreover, the protein expression of nephrin and podocin, podocyte markers, in glomeruli was increased in the AuNPs + D group compared with the D group. These results provide evidence that 50-nm AuNPs can ameliorate renal damage in experimental models of diabetic nephropathy through improving the renal function and downregulating extracellular matrix protein accumulation, along with inhibiting renal oxidative stress and amelioration of podocyte injury.
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Affiliation(s)
- Ghada Alomari
- Department of Bioscience, Faculty of Science, Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia.
- Department of Biological Sciences, Yarmouk University, Irbid, 21163, Jordan.
| | - Bahaa Al-Trad
- Department of Biological Sciences, Yarmouk University, Irbid, 21163, Jordan.
| | - Salehhuddin Hamdan
- Department of Bioscience, Faculty of Science, Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
| | - Alaa Aljabali
- Faculty of Pharmacy, Department of Pharmaceutical Sciences, Yarmouk University, Irbid, Jordan
| | - Mazhar Al-Zoubi
- Faculty of Medicine, Department of Basic Medical Sciences, Yarmouk University, Irbid, Jordan
| | - Nesreen Bataineh
- Faculty of Medicine, Department of Basic Medical Sciences, Yarmouk University, Irbid, Jordan
| | - Janti Qar
- Department of Biological Sciences, Yarmouk University, Irbid, 21163, Jordan
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Science, SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, County Londonderry, Northern Ireland, UK.
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A bigenic mouse model of FSGS reveals perturbed pathways in podocytes, mesangial cells and endothelial cells. PLoS One 2019; 14:e0216261. [PMID: 31461442 PMCID: PMC6713350 DOI: 10.1371/journal.pone.0216261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/12/2019] [Indexed: 11/24/2022] Open
Abstract
Focal segmental glomerulosclerosis is a major cause of end stage renal disease. Many patients prove unresponsive to available therapies. An improved understanding of the molecular basis of the disease process could provide insights leading to novel therapeutic approaches. In this study we carried out an RNA-seq analysis of the altered gene expression patterns of podocytes, mesangial cells and glomerular endothelial cells of the bigenic Cd2ap+/-, Fyn-/- mutant mouse model of FSGS. In the podocytes we observed upregulation of many genes related to the Tgfβ family/pathway, including Gdnf, Tgfβ1, Tgfβ2, Snai2, Vegfb, Bmp4, and Tnc. The mutant podocytes also showed upregulation of Acta2, a marker of smooth muscle and associated with myofibroblasts, which are implicated in driving fibrosis. GO analysis of the podocyte upregulated genes identified elevated protein kinase activity, increased expression of growth factors, and negative regulation of cell adhesion, perhaps related to the observed podocyte loss. Both podocytes and mesangial cells showed strong upregulation of aldehyde dehydrogenase genes involved in the synthesis of retinoic acid. Similarly, the Cd2ap+/-, Fyn-/- mesangial cells, as well as podocytes in other genetic models, and the glomeruli of human FSGS patients, all show upregulation of the serine protease Prss23, with the common thread suggesting important functionality. Another gene with strong upregulation in the Cd2ap+/-, Fyn-/- mutant mesangial cells as well as multiple other mutant mouse models of FSGS was thrombospondin, which activates the secreted inactive form of Tgfβ. The Cd2ap+/-, Fyn-/- mutant endothelial cells showed elevated expression of genes involved in cell proliferation, angioblast migration, angiogenesis, and neovasculature, all consistent with the formation of new blood vessels in the diseased glomerulus. The resulting global definition of the perturbed molecular pathways in the three major cell types of the mutant glomerulus provide deeper understanding of the molecular pathogenic pathways.
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15
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Zierfuss B, Höbaus C, Herz CT, Pesau G, Koppensteiner R, Schernthaner GH. Thrombospondin-4 increases with the severity of peripheral arterial disease and is associated with diabetes. Heart Vessels 2019; 35:52-58. [PMID: 31227875 PMCID: PMC6942020 DOI: 10.1007/s00380-019-01453-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/14/2019] [Indexed: 02/07/2023]
Abstract
Thrombospondin-4 (TSP-4) is an extracellular matrix protein of the vessel wall. Despite bench evidence, its significance in the clinical setting of atherosclerosis is missing. TSP-4 (ng/ml) was measured in 365 PAD patientsusing a commercially available ELISA. PAD was diagnosed by the ankle–brachial index (ABI) and clinically graded using the Fontaine classification. TSP-4 levels were significantly higher in Fontaine II vs. Fontaine I (4.78 ± 0. 42, 4.69 ± 0.42, p = 0.043). TSP-4 significantly correlated with ABI (r = − 0.141, p = 0.023, n = 259) after the exclusion of mediasclerotic patients. Binary logistic regression analysis for Fontaine I vs. II showed an OR of 1.70 (1.02–2.82) in a multivariable model adjusted for traditional risk factors. Interestingly, TSP-4 levels were higher in patients with type 2 diabetes mellitus or prediabetes (DGT) compared with normal glucose tolerance (NGT) (4.76 ± 0.42 vs. 4.66 ± 0.41, p = 0.035). ANOVA for PAD and diabetes subgroups showed a linear increase with disease burden with the highest difference between Fontaine I-NGT and Fontaine II-DGT (4.59 ± 0.40, 4.79 ± 0.43, p = 0.015). TSP-4 levels increased with PAD severity and showed a former unknown association with diabetes. Thus, TSP-4 could be a novel marker of atherosclerotic activity, especially in the major subgroup of patients with concomitant diabetes.
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Affiliation(s)
- Bernhard Zierfuss
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
| | - Clemens Höbaus
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Carsten T Herz
- Division of Endocrinology and Metabolism, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Gerfried Pesau
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Renate Koppensteiner
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Gerit-Holger Schernthaner
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
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16
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Bahrambeigi S, Rahimi M, Yousefi B, Shafiei-Irannejad V. New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications. J Cell Physiol 2019; 234:19393-19405. [PMID: 31004363 DOI: 10.1002/jcp.28682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications.
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Affiliation(s)
- Saman Bahrambeigi
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahdi Rahimi
- Ageing Research Institute, Physical Medicine and Rehabilitation Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Ageing Research Institute, Physical Medicine and Rehabilitation Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Shafiei-Irannejad
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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17
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Ekiz-Bilir B, Bilir B, Aydın M, Soysal-Atile N. Evaluation of endocan and endoglin levels in chronic kidney disease due to diabetes mellitus. Arch Med Sci 2019; 15:86-91. [PMID: 30697257 PMCID: PMC6348346 DOI: 10.5114/aoms.2018.79488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 11/09/2016] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Endocan and endoglin have been shown to play a role in angiogenesis. Aberrant excessive angiogenesis is a main factor in the development of diabetic nephropathy. In this study we evaluated endocan and endoglin levels in diabetes patients with and without albuminuria and compared them with healthy subjects. Therefore we aimed at gaining a better understanding of the role of angiogenesis in diabetic nephropathy and to assess the predictive role of endocan and endoglin as markers of diabetic nephropathy progression. MATERIAL AND METHODS Ninety-six type 2 diabetes patients were classified according to their 24-hour urinary albumin excretion rate. Forty type 2 diabetes patients with normoalbuminuria (urinary albumin excretion < 30 mg/day), 56 type 2 diabetes patients with diabetic nephropathy (with a urinary albumin excretion ≥ 30 mg/day) and 35 healthy non-diabetic control subjects were included. Their anthropometric features, arterial blood pressures, fasting glucose, glycated hemoglobin, urea, creatinine, lipids, endocan and endoglin levels were measured and compared to each other. RESULTS Endocan and endoglin levels of diabetics patients were higher than those of the controls. In comparison of endocan and endoglin levels of diabetic nephropathy patients with controls, p-values were < 0.001 and 0.002 respectively. In comparison of normoalbuminuric diabetic patients with controls, p-values were 0.001 and 0.017 respectively. Endocan levels of diabetic nephropathy cases were higher than those of normoalbuminuric patients (p = 0.011) but there was no statistically significant difference in endoglin levels between them (p = 0.822). CONCLUSIONS Endocan might be a more reliable marker of diabetic nephropathy development than endoglin.
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Affiliation(s)
- Betül Ekiz-Bilir
- Endocrinology and Metabolic Diseases Division, Tekirdag State Hospital, Tekirdag, Turkey
| | - Bülent Bilir
- Internal Medicine Department, Medical Faculty, Namik Kemal University, Tekirdağ, Turkey
| | - Murat Aydın
- Biochemistry Department, Medical Faculty, Namik Kemal University, Tekirdağ, Turkey
| | - Neslihan Soysal-Atile
- Endocrinology and Metabolic Diseases Division, Tekirdag State Hospital, Tekirdag, Turkey
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18
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Fernando KHN, Yang HW, Jiang Y, Jeon YJ, Ryu B. Diphlorethohydroxycarmalol Isolated from Ishige okamurae Represses High Glucose-Induced Angiogenesis In Vitro and In Vivo. Mar Drugs 2018; 16:E375. [PMID: 30308943 PMCID: PMC6215322 DOI: 10.3390/md16100375] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 10/04/2018] [Accepted: 10/05/2018] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus causes abnormalities of angiogenesis leading to vascular dysfunction and serious pathologies. Diphlorethohydroxycarmalol (DPHC), which is isolated from Ishige okamurae, is well known for its bioactivities, including antihyperglycemic and protective functions against diabetes-related pathologies. In the present study, the inhibitory effect of DPHC on high glucose-induced angiogenesis was investigated on the human vascular endothelial cell line EA.hy926. DPHC inhibited the cell proliferation, cell migration, and tube formation in cells exposed to 30 mM of glucose to induce angiogenesis. Furthermore, the effect of DPHC against high glucose-induced angiogenesis was evaluated in zebrafish embryos. The treatment of embryos with DPHC suppressed high glucose-induced dilation in the retinal vessel diameter and vessel formation. Moreover, DPHC could inhibit high glucose-induced vascular endothelial growth factor receptor 2 (VEGFR-2) expression and its downstream signaling cascade. Overall, these findings suggest that DPHC is actively involved in the suppression of high glucose-induced angiogenesis. Hence, DPHC is a potential agent for the development of therapeutics against angiogenesis induced by diabetes.
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Affiliation(s)
- K H N Fernando
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.
| | - Hye-Won Yang
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.
| | - Yunfei Jiang
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.
| | - BoMi Ryu
- Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.
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Chen PP, Xu HL, Ting-Yue, ZhuGe DL, Jin BH, Zhu QY, Shen BX, Wang LF, Lu CT, Zhao YZ, Li XK. CoQ10-loaded liposomes combined with UTMD prevented early nephropathy of diabetic rats. Oncotarget 2018; 9:11767-11782. [PMID: 29589596 PMCID: PMC5837748 DOI: 10.18632/oncotarget.24363] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 09/04/2017] [Indexed: 12/27/2022] Open
Abstract
Nephropathy is one of the most severe complications of diabetic patients. The therapeutic strategies for diabetic patients should not only focus on the control of blood glucose but also pay attention to the occurrence of diabetic nephropathy (DN). Coenzyme Q10 (CoQ10) has great therapeutic potential for DN. However, the clinical application of CoQ10 has been limited because of its low water-solubility and non-specific distribution. Liposomes were supposed to be an effective way for delivering CoQ10 to kidney. CoQ10 was effectively encapsulated into the liposome (CoQ10-LIP) with a high entrapment efficiency of 86.15 %. The CoQ10-LIP exhibited a small hydrodynamic diameter (180 ± 2.1 nm) and negative zeta potential (-18.20 mV). Moreover, CoQ10-LIP was combined with ultrasound-mediated microbubble destruction (UTMD) to enhance specific distribution of CoQ10 in kidney. In early stage of diabetic mellitus (DM), rats were administrated with CoQ10-LIP followed by UTMD (CoQ10-LIP+UTMD) to prevent occurrence of DN. Results revealed that CoQ10-LIP+UTMD effectively prevented the renal morphology and function of diabetics rats from damage. The protective mechanism of CoQ10-LIP was highly associated with protecting podocyte, promoting vascular repair and inhibiting cell apoptosis. Conclusively, CoQ10-LIP in combination with UTMD might be a potential strategy to prevent occurrence of DN.
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Affiliation(s)
- Pian-Pian Chen
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - He-Lin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Ting-Yue
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - De-Li ZhuGe
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Bing-Hui Jin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Qun-Yan Zhu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Bi-Xin Shen
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Li-Fen Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Cui-Tao Lu
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Ying-Zheng Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China.,The First Affiliated Hospital, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Xiao-Kun Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
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20
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Liu JJ, Pek SLT, Ang K, Tavintharan S, Lim SC. Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2017; 102:3683-3691. [PMID: 28973352 DOI: 10.1210/jc.2017-00930] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022]
Abstract
CONTEXT Abnormal angiogenesis plays an important role in pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a newly identified angiogenic factor. OBJECTIVE To study whether plasma LRG1 may independently predict progression of DKD in individuals with type 2 diabetes mellitus (T2DM). DESIGN AND SETTING Prospective cohort study in a regional hospital. PATIENTS In total, 1226 T2DM participants were followed for a mean ± standard deviation (SD) of 3.1 ± 0.4 years. MAIN OUTCOMES Albuminuria progression was defined as elevation in albuminuria level to a higher category. Chronic kidney disease (CKD) progression [rapid estimated glomerular filtration rate (eGFR) decline] was defined as a 40% or greater deterioration in eGFR in 3 years. RESULTS Both participants with albuminuria progression and those with CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted albuminuria progression above traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio. A 1-SD increment in LRG1 was associated with a 1.26-fold [95% confidence interval (CI), 1.04 to 1.53, P = 0.018] higher adjusted risk for albuminuria progression. The association of LRG1 with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria progression [odds ratio (OR), 1.51; 95% CI, 1.04 to 2.18, P = 0.029 vs OR, 1.09; 95% CI, 0.86 to 1.37, P = 0.486, per 1-SD LRG1 increment]. Also, LRG1 independently predicted CKD progression above traditional risk factors. A 1-SD increment in LRG1 was associated with a 1.48-fold (95% CI, 1.04 to 2.11, P = 0.032) higher adjusted risk for CKD progression. CONCLUSIONS Plasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM.
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Affiliation(s)
- Jian-Jun Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Sharon Li Ting Pek
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | - Kevin Ang
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore
| | | | - Su Chi Lim
- Diabetes Centre, Khoo Teck Puat Hospital, Singapore 768828, Singapore
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21
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Rudnicki M, Tripodi GL, Ferrer R, Boscá L, Pitta MGR, Pitta IR, Abdalla DSP. New thiazolidinediones affect endothelial cell activation and angiogenesis. Eur J Pharmacol 2016; 782:98-106. [PMID: 27108791 DOI: 10.1016/j.ejphar.2016.04.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 04/08/2016] [Accepted: 04/20/2016] [Indexed: 02/07/2023]
Abstract
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPARγ) agonists used in treating type 2 diabetes that may exhibit beneficial pleiotropic effects on endothelial cells. In this study, we characterized the effects of three new TZDs [GQ-32 (3-biphenyl-4-ylmethyl-5-(4-nitro-benzylidene)-thiazolidine-2,4-dione), GQ-169 (5-(4-chloro-benzylidene)-3-(2,6-dichloro-benzyl)-thiazolidine-2,4-dione), and LYSO-7 (5-(5-bromo-1H-indol-3-ylmethylene)-3-(4-chlorobenzyl)-thiazolidine-2,4-dione)] on endothelial cells. The effects of the new TZDs were evaluated on the production of nitric oxide (NO) and reactive oxygen species (ROS), cell migration, tube formation and the gene expression of adhesion molecules and angiogenic mediators in human umbilical vein endothelial cells (HUVECs). PPARγ activation by new TZDs was addressed with a reporter gene assay. The three new TZDs activated PPARγ and suppressed the tumor necrosis factor α-induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. GQ-169 and LYSO-7 also inhibited the glucose-induced ROS production. Although NO production assessed with 4-amino-5-methylamino-2',7'-difluorofluorescein-FM probe indicated that all tested TZDs enhanced intracellular levels of NO, only LYSO-7 treatment significantly increased the release of NO from HUVEC measured by chemiluminescence analysis of culture media. Additionally, GQ-32 and GQ-169 induced endothelial cell migration and tube formation by the up-regulation of angiogenic molecules expression, such as vascular endothelial growth factor A and interleukin 8. GQ-169 also increased the mRNA levels of basic fibroblast growth factor, and GQ-32 enhanced transforming growth factor-β expression. Together, the results of this study reveal that these new TZDs act as partial agonists of PPARγ and modulate endothelial cell activation and endothelial dysfunction besides to stimulate migration and tube formation.
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Affiliation(s)
- Martina Rudnicki
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo L Tripodi
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Renila Ferrer
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Marina G R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Ivan R Pitta
- Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil
| | - Dulcineia S P Abdalla
- Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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22
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Peng H, Li Y, Wang C, Zhang J, Chen Y, Chen W, Cao J, Wang Y, Hu Z, Lou T. ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy. Sci Rep 2016; 6:20304. [PMID: 26842599 PMCID: PMC4740844 DOI: 10.1038/srep20304] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/30/2015] [Indexed: 12/20/2022] Open
Abstract
Endothelial-to-mesenchymal transition (EndMT) can cause loss of tight junctions, which in glomeruli are associated with albuminuria. Here we evaluated the role of EndMT in the development of albuminuria in diabetic nephropathy (DN). We demonstrated that EndMT occurs in the glomerular endothelium of patients with DN, showing by a decrease in CD31 but an increase in α-SMA expression. In glomeruli of db/db mice, there was an increased ROCK1 expression in the endothelium plus a decreased CD31-positive cells. Cultured glomerular endothelial cells (GEnCs) underwent EndMT when stimulated by 30 mM glucose, and exhibited increased permeability. Meanwhile, they showed a higher ROCK1 expression and activation. Notably, inhibition of ROCK1 largely blocked EndMT and the increase in endothelial permeability under this high-glucose condition. In contrast, overexpression of ROCK1 induced these changes. Consistent alterations were observed in vivo that treating db/db mice with the ROCK1 inhibitor, fasudil, substantially suppressed the expression of α-SMA in the glomerular endothelium, and reduced albuminuria. Thus we conclude that ROCK1 is induced by high glucose and it stimulates EndMT, resulting in increased endothelial permeability. Inhibition of ROCK1 could be a therapeutic strategy for preventing glomerular endothelial dysfunction and albuminuria in developing DN.
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Affiliation(s)
- Hui Peng
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuanqing Li
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Cheng Wang
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jun Zhang
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanru Chen
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Wenfang Chen
- Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Jin Cao
- Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S
| | - Yanlin Wang
- Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S
| | - Zhaoyong Hu
- Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, 77030-3411, U.S
| | - Tanqi Lou
- Department of Internal Medicine, Nephrology Division, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
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23
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Downs CA, Faulkner MS. Toxic stress, inflammation and symptomatology of chronic complications in diabetes. World J Diabetes 2015; 6:554-565. [PMID: 25987953 PMCID: PMC4434076 DOI: 10.4239/wjd.v6.i4.554] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/30/2014] [Accepted: 02/12/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes affects at least 382 million people worldwide and the incidence is expected to reach 592 million by 2035. The incidence of diabetes in youth is skyrocketing as evidenced by a 21% increase in type 1 diabetes and a 30.5% increase in type 2 diabetes in the United States between 2001 and 2009. The effects of toxic stress, the culmination of biological and environmental interactions, on the development of diabetes complications is gaining attention. Stress impacts the hypothalamus-pituitary-adrenal axis and contributes to inflammation, a key biological contributor to the pathogenesis of diabetes and its associated complications. This review provides an overview of common diabetic complications such as neuropathy, cognitive decline, depression, nephropathy and cardiovascular disease. The review also provides a discussion of the role of inflammation and stress in the development and progression of chronic complications of diabetes, associated symptomatology and importance of early identification of symptoms of depression, fatigue, exercise intolerance and pain.
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Brunskill EW, Potter SS. Pathogenic pathways are activated in each major cell type of the glomerulus in the Cd2ap mutant mouse model of focal segmental glomerulosclerosis. BMC Nephrol 2015; 16:71. [PMID: 25968128 PMCID: PMC4430919 DOI: 10.1186/s12882-015-0063-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 05/01/2015] [Indexed: 11/29/2022] Open
Abstract
Background Mutations in several genes expressed in podocytes, including Cd2ap, have been associated with focal segmental glomerulosclerosis in humans. Mutant mouse models provide an opportunity to better understand the molecular pathology that drives these diseases. Methods In this report we use a battery of transgenic-GFP mice to facilitate the purification of all three major cell types of the glomerulus from Cd2ap mutant mice. Both microarrays and RNA-seq were used to characterize the gene expression profiles of the podocytes, mesangial cells and endothelial cells, providing a global dual platform cross-validating dataset. Results The mesangial cells showed increased expression of profibrotic factors, including thrombospondin, Tgfb2 and Tgfb3, as well as the angiogenesis factor Vegf. They also showed upregulation of protective genes, including Aldh1a2, involved in retinoic acid synthesis and Decorin, a Tgfb antagonist. Of interest, the mesangial cells also showed significant expression of Wt1, which has generally been considered podocyte specific. The Cd2ap mutant podocytes showed upregulation of proteases as well as genes involved in muscle and vasculature development and showed a very strong gene expression signature indicating programmed cell death. Endothelial cells showed increased expression of the leukocyte adhesion associated factors Vcam1 and Sele, as well as Midkine (promoting angiogenesis), endothelin and many genes responsive to cytokines and interferons. Conclusions This study provides a comprehensive analysis of the changing properties of the three cell types of the glomerulus in Cd2ap mutants, identifying activated and repressed pathways and responsible genes, thereby delivering a deeper molecular understanding of this genetic disease. Electronic supplementary material The online version of this article (doi:10.1186/s12882-015-0063-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Eric W Brunskill
- Cincinnati Children's Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
| | - S Steven Potter
- Cincinnati Children's Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
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Petroni K, Pilu R, Tonelli C. Anthocyanins in corn: a wealth of genes for human health. PLANTA 2014; 240:901-11. [PMID: 25106530 DOI: 10.1007/s00425-014-2131-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 07/18/2014] [Indexed: 05/24/2023]
Abstract
Different epidemiological and preclinical studies have demonstrated that regular consumption of anthocyanin-rich foods is associated to a reduced risk of chronic diseases, such as cardiovascular diseases, cancer and obesity. However, assigning a health property to anthocyanins or other classes of flavonoids may be limited by the influence of other metabolites of plant-based food consumed in the diet, acting as possible confounding factors. The development of model foods essentially isogenic and nutritionally identical except that in the type and quantity of plant bioactives to be studied represents an important tool in nutritional studies. The extensive knowledge of the regulation of flavonoid pathway in maize can be exploited to obtain 'near-isogenic' model foods, which differ only in the content of specific classes of flavonoids. Being obtainable by breeding strategies, maize model foods can provide functional foods that can be used for both animal feeding studies and human intervention trials for assessing the role of flavonoids or other bioactives in preventing chronic diseases. This review will be focused on recent advances regarding the anthocyanin biosynthesis in maize, the role of anthocyanins from corn in preventing chronic diseases and finally on the breeding activities to produce maize functional foods with increased anthocyanin content.
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Affiliation(s)
- Katia Petroni
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20133, Milan, Italy,
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Nazir N, Siddiqui K, Al-Qasim S, Al-Naqeb D. Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways. BMC MEDICAL GENETICS 2014; 15:103. [PMID: 25280384 PMCID: PMC4411872 DOI: 10.1186/s12881-014-0103-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 08/26/2014] [Indexed: 02/08/2023]
Abstract
Background Diabetes mellitus is the most common chronic endocrine disorder, affecting an estimated population of 382 million people worldwide. It is associated with microvascular and macrovascular complications, including diabetic nephropathy (DN); primary cause of end-stage renal disease. Different inflammatory and angiogenic molecules in various pathways are important modulators in the pathogenesis and progression of diabetic nephropathy. Differential disease risk in DN may be partly attributable to genetic susceptibility. In this meta-analysis, we aimed to determine which of the previously investigated genetic variants in these pathways are significantly associated with the development of DN and to examine the functional role of these genes. Methods A systematic search was conducted to collect and analyze all studies published till June 2013; that investigated the association between genetic variants involved in inflammatory cytokines and angiogenesis and diabetic nephropathy. Genetic variants associated with DN were selected and analyzed by using Comprehensive Meta Analysis software. Pathway analysis of the genes with variants showing significant positive association with DN was performed using Genomatix Genome Analyzer (Genomatix, Munich, Germany). Results After the inclusion and exclusion criteria for this analysis, 34 studies were included in this meta-analysis. 11 genetic variants showed significant positive association with DN in a random-effects meta-analysis. These included genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10. rs1800871 (T) genetic variant in IL-10 showed protective effect for DN. Most of these eleven genetic variants were involved in GPCR signaling and receptor binding pathways whereas four were involved in chronic kidney failure. rs833061 [OR 2.08 (95% CI 1.63-2.66)] in the VEGFA gene and rs3917887 [OR 2.04 (95% CI 1.64-2.54)] in the CCL2 gene showed the most significant association with the risk of diabetic nephropathy. Conclusions Our results indicate that 11 genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 showed significant positive association with diabetic nephropathy. Gene Ontology or pathway analysis showed that these genes may contribute to the pathophysiology of DN. The functional relevance of the variants and their pathways can lead to increased biological insights and development of new therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0103-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nyla Nazir
- Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia.
| | - Khalid Siddiqui
- Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia.
| | - Sara Al-Qasim
- Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia.
| | - Dhekra Al-Naqeb
- Strategic Center for Diabetes Research, King Saud University, P.O. Box 18397, Riyadh, 11415, K.S.A, Saudi Arabia.
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Roca F, Grossin N, Chassagne P, Puisieux F, Boulanger E. Glycation: the angiogenic paradox in aging and age-related disorders and diseases. Ageing Res Rev 2014; 15:146-60. [PMID: 24742501 DOI: 10.1016/j.arr.2014.03.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 03/26/2014] [Accepted: 03/31/2014] [Indexed: 01/09/2023]
Abstract
Angiogenesis is generally a quiescent process which, however, may be modified by different physiological and pathological conditions. The "angiogenic paradox" has been described in diabetes because this disease impairs the angiogenic response in a manner that differs depending on the organs involved and disease evolution. Aging is also associated with pro- and antiangiogenic processes. Glycation, the post-translational modification of proteins, increases with aging and the progression of diabetes. The effect of glycation on angiogenesis depends on the type of glycated proteins and cells involved. This complex link could be responsible for the "angiogenic paradox" in aging and age-related disorders and diseases. Using diabetes as a model, the present work has attempted to review the age-related angiogenic paradox, in particular the effects of glycation on angiogenesis during aging.
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Affiliation(s)
- F Roca
- Vascular Aging Biology, Blood-Vessel Interface and Vascular Repair Unit, Lille School of Medicine, Lille2 University, Lille, France; Geriatrics Department, Rouen University Hospital, Rouen, France.
| | - N Grossin
- Vascular Aging Biology, Blood-Vessel Interface and Vascular Repair Unit, Lille School of Medicine, Lille2 University, Lille, France
| | - P Chassagne
- Geriatrics Department, Rouen University Hospital, Rouen, France
| | - F Puisieux
- Vascular Aging Biology, Blood-Vessel Interface and Vascular Repair Unit, Lille School of Medicine, Lille2 University, Lille, France; Gerontology Clinic, Les Bateliers Geriatric Hospital, Lille University Hospital, Lille, France
| | - E Boulanger
- Vascular Aging Biology, Blood-Vessel Interface and Vascular Repair Unit, Lille School of Medicine, Lille2 University, Lille, France; Gerontology Clinic, Les Bateliers Geriatric Hospital, Lille University Hospital, Lille, France
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Kang MK, Lim SS, Lee JY, Yeo KM, Kang YH. Anthocyanin-rich purple corn extract inhibit diabetes-associated glomerular angiogenesis. PLoS One 2013; 8:e79823. [PMID: 24278186 PMCID: PMC3835931 DOI: 10.1371/journal.pone.0079823] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 10/04/2013] [Indexed: 01/05/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. Abnormal angiogenesis results in new vessels that are often immature and play a pathological role in DN, contributing to renal fibrosis and disrupting glomerular failure. Purple corn has been utilized as a daily food and exerts disease-preventive activities. This study was designed to investigate whether anthocyanin-rich purple corn extract (PCE) prevented glomerular angiogenesis under hyperglycemic conditions. Human endothelial cells were cultured in conditioned media of mesangial cells exposed to 33 mM high glucose (HG-HRMC-CM). PCE decreased endothelial expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α induced by HG-HRMC-CM. Additionally, PCE attenuated the induction of the endothelial marker of platelet endothelial cell adhesion molecule (PECAM)-1 and integrin β3 enhanced in HG-HRMC-CM. Endothelial tube formation promoted by HG-HRMC-CM was disrupted in the presence of PCE. In the in vivo study employing db/db mice treated with 10 mg/kg PCE for 8 weeks, PCE alleviated glomerular angiogenesis of diabetic kidneys by attenuating the induction of VEGF and HIF-1α. Oral administration of PCE retarded the endothelial proliferation in db/db mouse kidneys, evidenced by its inhibition of the induction of vascular endothelium-cadherin, PECAM-1 and Ki-67. PCE diminished the mesangial and endothelial induction of angiopoietin (Angpt) proteins under hypeglycemic conditions. The induction and activation of VEGF receptor 2 (VEGFR2) were dampened by treating PCE to db/db mice. These results demonstrate that PCE antagonized glomerular angiogenesis due to chronic hyperglycemia and diabetes through disturbing the Angpt-Tie-2 ligand-receptor system linked to renal VEGFR2 signaling pathway. Therefore, PCE may be a potent therapeutic agent targeting abnormal angiogenesis in DN leading to kidney failure.
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Affiliation(s)
- Min-Kyung Kang
- Department of Food and Nutrition and Center for Aging and Healthcare, Hallym University, Chuncheon, Korea
| | - Soon Sung Lim
- Department of Food and Nutrition and Center for Aging and Healthcare, Hallym University, Chuncheon, Korea
| | - Jae-Yong Lee
- Department of Biochemistry, School of Medicine, Hallym University, Chuncheon, Korea
| | | | - Young-Hee Kang
- Department of Food and Nutrition and Center for Aging and Healthcare, Hallym University, Chuncheon, Korea
- * E-mail:
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Zhou J, Zhou S. Inflammation: therapeutic targets for diabetic neuropathy. Mol Neurobiol 2013; 49:536-46. [PMID: 23990376 DOI: 10.1007/s12035-013-8537-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 08/15/2013] [Indexed: 11/26/2022]
Abstract
There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials.
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Affiliation(s)
- Jiyin Zhou
- National Drug Clinical Trial Institution, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China,
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Leong-Poi H. Contrast ultrasound and targeted microbubbles: diagnostic and therapeutic applications in progressive diabetic nephropathy. Semin Nephrol 2013; 32:494-504. [PMID: 23062991 DOI: 10.1016/j.semnephrol.2012.07.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetic nephropathy remains one of the most common causes for end-stage renal disease worldwide. Although therapies aimed at optimizing glycemic control and systemic blood pressure have benefit, the reduction in progressive nephropathy remains modest at best. Thus, research continues to focus on newer therapies to address the unmet needs for additional renal protective strategies. The ability to noninvasively image the molecular and cellular processes that underlie diabetic nephropathy would be useful in risk stratifying patients with diabetes, and more importantly would aid in the evaluation of novel therapies to prevent and treat nephropathy. In addition, the development of ultrasound technologies that allow targeted gene delivery using high-power ultrasound and DNA-bearing microbubbles may have applicability for gene therapy to prevent diabetic nephropathy. This review highlights contrast-enhanced ultrasound imaging techniques for the evaluation of renal pathologies, including perfusion and molecular imaging techniques, and ultrasound-mediated gene delivery for therapeutic applications in diabetic nephropathy, that have potential for translation to clinical practice.
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Affiliation(s)
- Howard Leong-Poi
- Division of Cardiology, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
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Abstract
Vascular endothelial dysfunction is determined by both genetic and environmental factors that cause decreased bioavailability of the vasodilator nitric oxide. This is a hallmark of atherosclerosis, hypertension, and coronary heart disease, which are major complications of metabolic disorders, including diabetes and obesity. Several therapeutic interventions, including changes in lifestyle as well as pharmacologic treatments, are useful for improving endothelial dysfunction in the face of lipotoxicity. This review discusses the current understanding of molecular and physiologic mechanisms underlying lipotoxicity-mediated endothelial dysfunction as well as relevant therapeutic approaches to ameliorate dyslipidemia and consequent endothelial dysfunction that have the potential to improve cardiovascular and metabolic outcomes.
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Affiliation(s)
- Jeong-a Kim
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, 1808 7th Avenue South, BDB 777, Birmingham, AL 35294-0012, USA
- Department of Cell Biology, University of Alabama at Birmingham, 1808 7th Avenue South, BDB 777, Birmingham, AL 35294, USA
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University “Aldo Moro” at Bari, Policlinico, Piazza G. Cesare, 11, 70124 Bari, Italy
| | - Sruti Chandrasekran
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, 660 West Redwood Street, HH 495, Baltimore, MD 21201, USA
| | - Michael J. Quon
- Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, 660 West Redwood Street, HH 495, Baltimore, MD 21201, USA
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Celec P, Hodosy J, Gardlík R, Behuliak M, Pálffy R, Pribula M, Jáni P, Turňa J, Sebeková K. The effects of anti-inflammatory and anti-angiogenic DNA vaccination on diabetic nephropathy in rats. Hum Gene Ther 2012; 23:158-66. [PMID: 21939398 DOI: 10.1089/hum.2011.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Inflammation and angiogenesis play a crucial role in the pathomechanism of diabetic nephropathy. Monocyte chemoattractant protein 1 (MCP) is a key regulator of the immune system in kidneys, and its inhibition with a dominant-negative mutant lacking the N-terminal amino acids 2-8 (7ND) reduces renal fibrosis. Angiomotin (Amot) is a novel angiogenesis modulator. We studied the effects of inhibition of Amot and MCP using DNA vaccination on incipient diabetic nephropathy in rats. Plasmid DNA (with either 7ND or human Amot) was electroporated twice into hind-limb muscles of rats with streptozotocin-induced diabetes mellitus. Sham-electroporated diabetic rats and healthy animals served as controls. After 4 months, renal histology and biochemical analyses were performed. In sham-electroporated diabetic rats, glomerular histology revealed pathological changes. 7ND and Amot treatments reduced glomerular hypertrophy and periodic acid-Schiff positivity. In both treated groups, the expression of profibrotic (transforming growth factor-β, collagen 1), proinflammatory (interleukin-6, tumor necrosis factor-α), and proangiogenic (vascular endothelial growth factor) genes in the renal cortex was lower than in the diabetic group without treatment. The mentioned renoprotective effects could be mediated via higher total antioxidant capacity and improved glycemic control. Anti-angiogenic and anti-inflammatory DNA vaccination ameliorates the progression of glomerular pathology in an animal model of diabetic nephropathy.
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Affiliation(s)
- Peter Celec
- Institute of Molecular Biomedicine, Comenius University , 811 08 Bratislava, Slovakia.
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Abstract
In patients with diabetes, nerve injury is a common complication that leads to chronic pain, numbness and substantial loss of quality of life. Good glycemic control can decrease the incidence of diabetic neuropathy, but more than half of all patients with diabetes still develop this complication. There is no approved treatment to prevent or halt diabetic neuropathy, and only symptomatic pain therapies, with variable efficacy, are available. New insights into the mechanisms leading to the development of diabetic neuropathy continue to point to systemic and cellular imbalances in metabolites of glucose and lipids. In the PNS, sensory neurons, Schwann cells and the microvascular endothelium are vulnerable to oxidative and inflammatory stress in the presence of these altered metabolic substrates. This Review discusses the emerging cellular mechanisms that are activated in the diabetic milieu of hyperglycemia, dyslipidemia and impaired insulin signaling. We highlight the pathways to cellular injury, thereby identifying promising therapeutic targets, including mitochondrial function and inflammation.
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Markiewicz M, Nakerakanti SS, Kapanadze B, Ghatnekar A, Trojanowska M. Connective tissue growth factor (CTGF/CCN2) mediates angiogenic effect of S1P in human dermal microvascular endothelial cells. Microcirculation 2011; 18:1-11. [PMID: 21166920 DOI: 10.1111/j.1549-8719.2010.00058.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The primary objective of this study was to examine the potential interaction between S1P, a pleiotropic lipid mediator, and CTGF/CCN2, a secreted multimodular protein, in the process of endothelial cell migration. The secondary objective was to determine whether C- and N-terminal domains of CTGF/CCN2 have a specific function in cell migration. MATERIALS AND METHODS Migration of HDMECs was examined in monolayer wound healing "scratch" assay, whereas capillary-like tube formation was examined in three-dimensional collagen co-culture assays. RESULTS We observed that S1P stimulates migration of HDMECs concomitant with upregulation of CTGF/CCN2 expression. Furthermore, the blockade of endogenous CTGF/CCN2 via siRNA abrogated S1P-induced HDMEC migration and capillary-like tube formation. Full-length CTGF induced cell migration and capillary-like tube formation with a potency similar to that of S1P, while C-terminal domain of CTGF was slightly less effective. However, N-terminal domain had only a residual activity in inducing capillary-like tube formation. CONCLUSIONS This study revealed that CTGF/CCN2 is required for the S1P-induced endothelial cell migration, which suggests that CTGF/CCN2 may be an important mediator of S1P-induced physiological and pathological angiogenesis. Moreover, this study shows that the pro-migratory activity of CTGF/CCN2 is located in the C-terminal domain.
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Affiliation(s)
- Margaret Markiewicz
- Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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Mayer G. Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease. Nephrol Dial Transplant 2011; 26:1132-7. [PMID: 21330358 PMCID: PMC3070072 DOI: 10.1093/ndt/gfq832] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Tubulointerstitial hypoxia and peritubular capillary rarefaction are typical features of chronic progressive renal disease. In response to low oxygen supply, hypoxia-inducible factors (HIFs) are activated but until now, it is unclear if this increased expression leads to a stabilization of the disease process and thus is nephroprotective or contributes to interstitial fibrosis and/or tubular atrophy. This duality has also been described as far as vascular endothelial growth factor (VEGF), one of the major target genes of HIFs, is concerned. On the one hand, neoangiogenesis driven by VEGF, if intact, ameliorates hypoxia, on the other, VEGF is a potent pro-inflammatory mediator and neoangiogenesis, if defective because interference by other pathologies exaggerates injury. In summary, experimental data support the idea that dependent on timing and predominant pathology, hypoxia counter-regulatory factors exert beneficial or undesirable effects. Thus, before their therapeutic potential can be fully explored, a better way to characterize the clinical and pathophysiological situation in an individual patient is mandatory.
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Affiliation(s)
- Gert Mayer
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria.
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Gene expression programs of mouse endothelial cells in kidney development and disease. PLoS One 2010; 5:e12034. [PMID: 20706631 PMCID: PMC2919381 DOI: 10.1371/journal.pone.0012034] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Accepted: 07/11/2010] [Indexed: 12/25/2022] Open
Abstract
Endothelial cells are remarkably heterogeneous in both morphology and function, and they play critical roles in the formation of multiple organ systems. In addition endothelial cell dysfunction can contribute to disease processes, including diabetic nephropathy, which is a leading cause of end stage renal disease. In this report we define the comprehensive gene expression programs of multiple types of kidney endothelial cells, and analyze the differences that distinguish them. Endothelial cells were purified from Tie2-GFP mice by cell dissociation and fluorescent activated cell sorting. Microarrays were then used to provide a global, quantitative and sensitive measure of gene expression levels. We examined renal endothelial cells from the embryo and from the adult glomerulus, cortex and medulla compartments, as well as the glomerular endothelial cells of the db/db mutant mouse, which represents a model for human diabetic nephropathy. The results identified the growth factors, receptors and transcription factors expressed by these multiple endothelial cell types. Biological processes and molecular pathways were characterized in exquisite detail. Cell type specific gene expression patterns were defined, finding novel molecular markers and providing a better understanding of compartmental distinctions. Further, analysis of enriched, evolutionarily conserved transcription factor binding sites in the promoters of co-activated genes begins to define the genetic regulatory network of renal endothelial cell formation. Finally, the gene expression differences associated with diabetic nephropathy were defined, providing a global view of both the pathogenic and protective pathways activated. These studies provide a rich resource to facilitate further investigations of endothelial cell functions in kidney development, adult compartments, and disease.
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Metabolic syndrome: Aggression control mechanisms gone out of control. Med Hypotheses 2010; 74:578-89. [DOI: 10.1016/j.mehy.2009.09.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 09/07/2009] [Indexed: 01/13/2023]
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Abstract
PURPOSE OF REVIEW The prevalence of chronic kidney disease has been growing consistently for the past decades. Renal failure is often associated with defective angiogenesis, and recognition of the contribution of the renal microcirculation to the progression of chronic renal disease may aid in the development of therapeutic interventions. RECENT FINDINGS Intra-renal proliferation, remodeling, and/or rarefaction of microvessels in response to injury can all aggravate nephron damage, and experimental evidence suggests that they may constitute the early steps in the complex pathways involved in progressive renal injury. Recent studies showed the benefits of targeted interventions deemed to promote neovascularization (e.g. progenitor cells, growth factors) on the ischemic myocardium and brain and in a few models of renal disease. SUMMARY Evidence of aberrant renal microvascular architecture in various forms of renal disease provides the impetus to attempt modulating the renal microcirculation to interfere with the disease process. Targeted interventions to preserve the renal microcirculation may not only decrease the evolving injury in renal vascular disease but also potentially constitute a coadjuvant intervention to become part of a comprehensive management plan to improve the success of parallel strategies to preserve renal function, such as revascularization.
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