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Zhang X, Wang G, Li M, Li Y, Luo X, Liu Y, Zhang X, Hocher JG, Krämer BK, Hocher B, Yang X. Both partial inactivation as well as activation of NF-κB signaling lead to hypertension and chronic kidney disease. Nephrol Dial Transplant 2024; 39:1993-2004. [PMID: 38614958 DOI: 10.1093/ndt/gfae090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND Activation of nuclear factor-kappa B (NF-κB) signalling is key in the pathogenesis of chronic kidney disease (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS The relationship between activated and inactivated NF-κB signaling and the pathogenesis of CKD was investigated using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS The density of CD3, CD8, CD68 positive cells, as well as the expression of interleukin 6, Tumor necrosis factor receptor associated factor 1 and Nef-associated factor 1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by periodic acid-Schiff, Masson trichrome and Sirius Red staining, as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine ratio are markedly increased in NF-κB-activated and -inactivated mice compared with controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared with wild-type mice. CONCLUSIONS Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.
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Affiliation(s)
- Xiaotan Zhang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
- Department of Pathology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Guang Wang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
- Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, China
| | - Ming Li
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
| | - Yunjin Li
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
| | - Xin Luo
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
| | - Yvonne Liu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology, Pneumology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
- Medical Faculty of Charité University Berlin, Berlin, Germany
| | - Xiaoli Zhang
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology, Pneumology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Johann-Georg Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology, Pneumology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
- Second Medical Faculty, Charles University Prague, Prague, Czech Republic
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology, Pneumology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology, Pneumology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
- Reproductive, Genetic Hospital of CITIC-Xiangya, Changsha, China, Institute of Medical Diagnostics, IMD, Berlin, Germany
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China
| | - Xuesong Yang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Clinical Research Center, Clifford Hospital, Guangzhou, China
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Anilkumar S A, Dutta S, Aboo S, Ismail A. Vitamin D as a modulator of molecular pathways involved in CVDs: Evidence from preclinical studies. Life Sci 2024; 357:123062. [PMID: 39288869 DOI: 10.1016/j.lfs.2024.123062] [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: 06/18/2024] [Revised: 08/27/2024] [Accepted: 09/12/2024] [Indexed: 09/19/2024]
Abstract
Vitamin D deficiency (VDD) is a widespread global health issue, affecting nearly a billion individuals worldwide, and mounting evidence links it to an increased risk of cardiovascular diseases like hypertension, atherosclerosis, and heart failure. The discovery of vitamin D receptors and metabolizing enzymes in cardiac and vascular cells, coupled with experimental studies, underscores the complex relationship between vitamin D and cardiovascular health. This review aims to synthesize and critically evaluate the preclinical evidence elucidating the role of vitamin D in cardiovascular health. We examined diverse preclinical in vitro (cardiomyocyte cell line) models and in vivo models, including knockout mice, diet-induced deficiency, and disease-specific animal models (hypertension, hypertrophy and myocardial infarction). These studies reveal that vitamin D modulates vascular tone, and prevents fibrosis and hypertrophy through effects on major signal transduction pathways (NF-kB, Nrf2, PI3K/AKT/mTOR, Calcineurin/NFAT, TGF-β/Smad, AMPK) and influences epigenetic mechanisms governing inflammation, oxidative stress, and pathological remodeling. In vitro studies elucidate vitamin D's capacity to promote cardiomyocyte differentiation and inhibit pathological remodeling. In vivo studies further uncovered detrimental cardiac effects of VDD, while supplementation with vitamin D in cardiovascular disease (CVD) models demonstrated its protective effects by decreasing inflammation, attenuating hypertrophy, reduction in plaque formation, and improving cardiac function. Hence, this comprehensive review emphasizes the critical role of vitamin D in cardiovascular health and its potential as a preventive/therapeutic strategy in CVDs. However, further research is needed to translate these findings into clinical applications as there are discrepancies between preclinical and clinical studies.
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Affiliation(s)
- Athira Anilkumar S
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, India
| | - Soumam Dutta
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, India
| | - Shabna Aboo
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, India.
| | - Ayesha Ismail
- Department of Endocrinology, ICMR-National Institute of Nutrition, Hyderabad, India.
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Wang C, Zheng Y, Fan Q, Li Z, Qi X, Chen F, Xu L, Zhou S, Chen X, Li Y, Zhu J, Su C. MIR-155 PROMOTES ACUTE ORGAN INJURY IN LPS-INDUCED ENDOTOXEMIC MICE BY ENHANCING CCL-2 EXPRESSION IN MACROPHAGES. Shock 2024; 61:611-619. [PMID: 37878486 DOI: 10.1097/shk.0000000000002236] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023]
Abstract
ABSTRACT Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Macrophages play important roles in the inflammatory process of sepsis by secreting chemokines. Chemokine (CC-motif) ligand 2 (CCL-2) is one of the main proinflammatory chemokines secreted by macrophages that plays a critical role in the recruitment of more monocytes and macrophages to the sites of injury in sepsis, but the mechanisms that regulate CCL-2 expression in macrophages during sepsis are still unknown. In the present study, by using the LPS-induced endotoxemia model, we found that LPS induced the expression of microRNA (miR)-155 and CCL-2 in endotoxemic mice and RAW264.7 cells. MiR-155 mimics or miR-155 inhibitor treatment experiment suggested that miR-155 was sufficient to increase LPS-induced CCL-2 expression in macrophages, but miR-155 was not the only factor promoting CCL-2 expression. We further demonstrated that miR-155-induced increase of CCL-2 promoted chemotaxis of additional macrophages, which subsequently enhanced lung injury in endotoxemic mice. Serum/glucocorticoid regulated kinase family member 3 (SGK3), a potential target of miR-155, was identified by RNA sequencing and predicted by TargetScan and miRDB. We further confirmed miR-155 regulated SGK3 to increase LPS-induced CCL-2 by using miR-155 mimics and SGK3 overexpression. Thus, our study demonstrates that miR-155 targets SGK3 to increase LPS-induced CCL-2 expression in macrophages, which promotes macrophage chemotaxis and enhances organs injury during endotoxemia. Our study contributed to a better understanding of the mechanisms underlying the inflammatory response during sepsis.
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Affiliation(s)
- Chun Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, National Vaccine Innovation Platform of Nanjing Medical University, Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
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V. P. Komisarenko Institute of Endocrinology and Metabolism,National Academy of Medical Sciences of Ukraine, Kyiv, Zak KP, Tronko MD, V. P. Komisarenko Institute of Endocrinology and Metabolism,National Academy of Medical Sciences of Ukraine, Kyiv, Komisarenko SV, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv. Immunological mechanisms of increased susceptibility to COVID-19 disease and its severe course in patients with diabetes mellitus type 2 and obesity. UKRAINIAN BIOCHEMICAL JOURNAL 2023; 95:5-23. [DOI: 10.15407/ubj95.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
In this review, we analyze and summarize literature data and the results of our own research related to the immunity status of patients with type 2 diabetes mellitus (T2D) and those T2D patients who were infected with the SARS-CoV-2 virus. It was shown that in the blood plasma of T2D patients, especially those with elevated BMI, the level and ultrastructure of the main cellular components of natural immunity – neutrophils and monocytes – were affected accompanied by high levels of proinflammatory cytokines (IL-1β, IL-6, IL-17 and TNF-α). It was suggested that the increased susceptibility of T2D patients to SARS-CoV-2 infection is primarily due to a weakening of the innate immune defense against pathogens, whereas in T2D patients who have COVID-19, adaptive T-cell immunity disorders accompanied by a cytokine storm prevail. It was concluded that hyperinflammation in T2D+COVID19 patients is the result of enhancement of already existing before SARS-CoV-2 infection T2D-caused disorders of innate and adaptive immunity, in the mechanism of which cytokines and chemokines play a significant role. Keywords: COVID-19, cytokines, innate and adaptive immunit, neutrophils, T-lymphocytes, type 2 diabetes mellitus
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Chen X, Wan Z, Geng T, Zhu K, Li R, Lu Q, Lin X, Liu S, Chen L, Guo Y, Shan Z, Liu L, Pan A, Manson JE, Liu G. Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes: A Prospective Study. Diabetes Care 2023; 46:270-277. [PMID: 36169213 DOI: 10.2337/dc22-0513] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/29/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Evidence is limited regarding the associations between vitamin D status and microvascular complications in individuals with type 2 diabetes (T2D), among whom vitamin D deficiency or insufficiency is particularly common. In this study we aimed to prospectively investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] and vitamin D receptor (VDR) polymorphisms with risk of diabetic microvascular complications. RESEARCH DESIGN AND METHODS This analysis included 14,709 participants with T2D who were free of microvascular complications from the UK Biobank. Incidence of diabetic microvascular complications was ascertained via electronic health records. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS Median serum 25(OH)D concentration was 40.7 nmol/L (interquartile range 27.5, 56.4). During a median of 11.2 years of follow-up, 1,370 people developed diabetic microvascular complications. Compared with participants with 25(OH)D <25 nmol/L, individuals with 25(OH)D ≥75 nmol/L had a multivariable-adjusted HR of 0.65 (95% CI 0.51, 0.84) for composite diabetic microvascular complications, 0.62 (0.40, 0.95) for diabetic retinopathy, 0.56 (0.40, 0.79) for diabetic nephropathy, and 0.48 (0.26, 0.89) for diabetic neuropathy. In addition, in comparisons with participants with 25(OH)D <25 nmol/L and minor allele homozygotes (TT of rs1544410 and GG of rs731236), the multivariable-adjusted HRs of composite diabetic microvascular complications were 0.54 (0.38, 0.78) and 0.55 (0.38, 0.80) for participants with serum 25(OH)D ≥50 nmol/L and major allele homozygotes (CC and AA), respectively, although no significant interaction was observed. CONCLUSIONS Higher serum 25(OH)D concentrations were significantly associated with lower risk of diabetic microvascular complications, including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Our findings suggest a potential beneficial role of maintaining adequate vitamin D status in the prevention of diabetic microvascular complications.
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Affiliation(s)
- Xue Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenzhen Wan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Geng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Lu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Lin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sen Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liangkai Chen
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanjun Guo
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhilei Shan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - An Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - JoAnn E Manson
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Gang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Lab of Environment and Health, and State Key Laboratory of Environment Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Guo X, Li Y, Wang W, Wang L, Hu S, Xiao X, Hu C, Dai Y, Zhang Y, Li Z, Li J, Ma X, Zeng J. The construction of preclinical evidence for the treatment of liver fibrosis with quercetin: A systematic review and meta-analysis. Phytother Res 2022; 36:3774-3791. [PMID: 35918855 DOI: 10.1002/ptr.7569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/06/2022] [Accepted: 07/06/2022] [Indexed: 12/09/2022]
Abstract
Quercetin (3,3',4',5,7-pentahydroxyflavone), a flavonoid, is widely found in fruits and vegetables and exerts broad-spectrum pharmacological effects in the liver. Many studies have explored the bioactivity of quercetin in the treatment of liver fibrosis. Hence, through a systematic review and biological mechanism evaluation, this study aimed to construct a body of preclinical evidence for the treatment of liver fibrosis using quercetin. The literature used in this study was mainly obtained from four databases, and the SYRCLE list (10 items) was used to evaluate the quality of the included literature. A meta-analysis of HA, LN, and other indicators was performed via STATA 15.0 software. Subgroup analyses based on animal species and model protocol were performed to further obtain detailed results. Moreover, the therapeutic mechanism of quercetin was summarized in a directed network form based on a comprehensive search of the literature. After screening, a total of 14 articles (comprising 15 studies) involving 254 animals were included. The results from the analysis showed that the corresponding liver function indexes, such as the levels of HA and LN, were significantly improved in the quercetin group compared with the model group, and liver function, such as the levels of AST and ALT, were also improved in the quercetin group. The species- and model-based subgroup analyses of AST and ALT revealed that quercetin exerts a significant effect. The therapeutic mechanism of quercetin was shown to be related to multiple pathways involving anti-inflammatory and antioxidant activities and lipid accumulation, including regulation of the TGF-β, α-SMA, ROS, and P-AMPK pathways. The results showed that quercetin exerts an obvious effect on liver fibrosis, and more prominent improvement effects on liver function and liver fibrosis indicators were obtained with a dose of 5-200 mg during a treatment course ranging from 4 to 8 weeks. Quercetin might be a promising therapeutic for liver fibrosis.
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Affiliation(s)
- Xiaochuan Guo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Weizheng Wang
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Luyao Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sihan Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Caiyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yao Dai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiheng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ziyu Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Junlin Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Huang B, Wen W, Ye S. Correlation Between Serum 25-Hydroxyvitamin D Levels in Albuminuria Progression of Diabetic Kidney Disease and Underlying Mechanisms By Bioinformatics Analysis. Front Endocrinol (Lausanne) 2022; 13:880930. [PMID: 35634488 PMCID: PMC9133500 DOI: 10.3389/fendo.2022.880930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/11/2022] [Indexed: 01/07/2023] Open
Abstract
AIM This study aimed to assess the correlation between serum concentration of 25-hydroxyvitamin D and albuminuria progression of diabetic kidney disease (DKD) and to use bioinformatics methods to determine the potential mechanism in the pathological process of advanced DKD. METHODS A total of 178 type 1 diabetes mellitus (T1DM) patients with microalbuminuria complications who were hospitalized at least twice (with an interval > 24 months) in the Department of Endocrinology of The First Affiliated Hospital of USTC were included in this study. According to the urinary albumin creatinine ratio (UACR), we classified DKD stages as follows: microalbuminuria (UACR, 30-300 mg/g), and macroalbuminuria (UACR, >300 mg/g). We divided the patients into DKD progression (N=44) and stable group (N=134) on account of urinary albumin-to-creatinine ratio (UACR) by at least two randomized measurements. Stable group was defined as UACR between 30 and 300 mg/g, whereas progression group was defined as UACR >300 mg/g at the end of follow-up. Data were obtained from participants' medical records, and the 25-hydroxyvitamin D level was categorized into three groups as follows: G1 (N=45), <10 ng/mL; G2 (N=80), 10-20 ng/ml; and G3 (N=53), ≥20 ng/mL. The Nephroseq database (http://v5.nephroseq.org) was used to identify VDR expression in diabetic nephropathy. The dataset GSE142025 from GEO (http://www.ncbi.nlm.nih.gov/geo) was downloaded. After stratification by the median-centered log2 VDR expression value, the 21 advanced DKD samples were divided into two groups (low VDR expression group and high VDR expression group). Gene set enrichment analysis (GSEA) (http://software.broadinstitute.org/gsea/index.jsp). Differentially expressed genes (DEGs) were screened by the limma package (adjusted p < 0.05, |logFC| > 1). The Gene Ontology (GO; http://www.geneontology.org/) database and pathway analysis within the Kyoto Encyclopedia of Genes and Genomes (KEGG; https://www.kegg.jp/) were performed using the R package ClusterProfile. The CIBERSORT (Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts) algorithm was utilized for calculating the infiltrated immune cells in advanced kidney tissues. RESULTS 1) A multivariate Cox regression analysis revealed that DR (diabetic retinopathy), eGFR (estimated glomerular filtration rate), and 25-hydroxyvitamin D were significant independent predictors of DKD progression (HR: 2.57, 95% CI: 1.44.4.24, p=0.007; HR: 2.13, 95% CI: 1.58.3.79, p = 0.011; HR: 0.732, 95% CI: 0.232-0.816, p = 0.023, respectively). 2) Kaplan-Meier survival curves of DKD progression by serum 25-hydroxyvitamin D stratification showed that the G2 and G3 groups were significantly different when compared with the G1 group (log-rank χ2 = 14.69, p <0.001; χ2 = 28.26, p <0.001, respectively). 3) There was a weak negative correlation between 25-hydroxyvitamin D level and UACR at baseline,and the overall mean rate of change in eGFR was 1.121 ± 0.19 ml/min/1.73 m2/year. Neither crude nor adjusted rate of decline in eGFR was significantly different among patients classified according to baseline serum 25-hydroxyvitamin D levels (all p<0.05). 4) The high expression of VDR group was most positively correlated with enriched gene sets like reactome innate immune system and reactome G alpha I signaling events when compared with the low expression of VDR group. 5) The CIBERSORT algorithm showed decreased M2 macrophage infiltration in advanced kidneys in comparison to low VDR expression and high VDR expression. CONCLUSION This study concluded that low 25-hydroxyvitamin D levels can predict an increased risk of DKD albuminuria progression and eGFR decline. Decreased M2 macrophage infiltration may be a potential mechanism involved in this pathogenesis.
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Affiliation(s)
- Bin Huang
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenjie Wen
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Department of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
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Lack of association between methylation status of CpG in the MCP-1 promoter and type 2 diabetes mellitus and its complications in a Moroccan population. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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9
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Zouhal H, Zare-Kookandeh N, Haghighi MM, Daraei A, de Sousa M, Soltani M, Abderrahman AB, M Tijani J, Hackney AC, Laher I, Saeidi A. Physical activity and adipokine levels in individuals with type 2 diabetes: A literature review and practical applications. Rev Endocr Metab Disord 2021; 22:987-1011. [PMID: 33931803 DOI: 10.1007/s11154-021-09657-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
We review the effects of acute and long-term physical activity on adipokine levels in individuals with type 2 diabetes (T2D). Three electronic databases were searched. Studies made in animal models were excluded, while studies based on participants with and without T2D, and also studies with type 1 diabetes were included. Of the 2,450 citations, 63 trials, including randomised control trials, cross-sectional and longitudinal studies, met our inclusion criteria. Seventy and five percent of studies reported the effects of physical activity on tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), adiponectin, visfatin, omentin-1, and leptin levels. There are no robust results due to variations in exercise modality, intensity, duration, and also differences in cohort characteristics in the literature. Only four studies described the effects of an acute session of physical activity on adipokine levels. Overall, physical activity improves diabetes status by regulating adipokine levels. However, long-term aerobic + resistance training combined with dietary modifications is likely to be a more effective strategy for improving adipokines profiles in patients with type 2 diabetes.
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Affiliation(s)
- Hassane Zouhal
- M2S (Laboratoire Mouvement, University of Rennes, 1274, F-35000, Sport, Santé), France.
| | | | | | - Ali Daraei
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | - Mohammad Soltani
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | | | - Anthony C Hackney
- Department of Exercise & Sport Science, Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
| | - Ismail Laher
- Faculty of Medicine, Department of Anesthesiology, The University of British Columbia, Pharmacology & Therapeutics, Vancouver, Canada
| | - Ayoub Saeidi
- Department of Physical Education and Sport Sciences, University of Kurdistan, Sanandaj, Iran.
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Zak K, Popova V, Orlenko V, Furmanova O, Tronko N. Cytokines in the blood of patients with type 2 diabetes mellitus depending on the level of overweight/obesity (literature review and own data). INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:534-551. [DOI: 10.22141/2224-0721.17.7.2021.244969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The paper analyzes the current literature data and the results of our own researches concerning the state of the cytokine network: pro- and anti-inflammatory cytokines (interleukin (IL)1α, IL-1β, IL-4, IL-6, IL-10, IL-17 and tumor necrosis factor (TNF) α), α- and β-chemokines, including IL-8 and IL-16, as well as adipokines (leptin and adiponectin) in the peripheral blood of patients with type 2 diabetes (T2D) with normal and increased body weight/obesity. It has been shown that patients with T2D are characterized by an increased content of proinflammatory cytokines (IL-1, IL-6, IL-17, TNFα), α- and β-chemokines in the peripheral blood, including IL-8 and IL-16, as well as leptin with a decrease in adiponectin content. In lean patients (with body mass index (BMI)<25.5 kg/m2) compared to lean normoglycemic individuals from the control group (BMI<25.5kg/m2), there is a small but significant increase in IL-1β, IL-6, IL-17, TNFα and leptin, which, as BMI increases, significantly increases in severe obesity (BMI>30.0kg/m2), especially in obese women (BMI>35.0kg/m2). Similarly, an increase in proinflammatory cytokines is observed in normoglycemic people, but not as significant as in T2D. Less clear data were obtained when during determination of the anti-inflammatory cytokines IL-4 and IL-10, which is explained by a significant polymorphism of their genes, and both protective and compensatory effects on pro-inflammatory cytokine rise. In T2D patients, especially those with obesity, there is an increase in the leptin level and a decrease in the adiponectin content. The severity of the course and the percentage of mortality are closely associated with the BMI of patients. The effectiveness of the fight against an increase in the incidence of T2D should be primarily aimed at preventing obesity, and in case of already developed T2D— at reducing concomitant obesity. The analysis of the data presented also suggests that a sharp increase in the content of pro-inflammatory cytokines (so called cytokine storm) observed in patients with T2D and obesity infected with COVID-19, is a consequence of the summation and potentiation of already existing inflammatory process.
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Development of Biomarkers and Molecular Therapy Based on Inflammatory Genes in Diabetic Nephropathy. Int J Mol Sci 2021; 22:ijms22189985. [PMID: 34576149 PMCID: PMC8465809 DOI: 10.3390/ijms22189985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic Nephropathy (DN) is a debilitating consequence of both Type 1 and Type 2 diabetes affecting the kidney and renal tubules leading to End Stage Renal Disease (ESRD). As diabetes is a world epidemic and almost half of diabetic patients develop DN in their lifetime, a large group of people is affected. Due to the complex nature of the disease, current diagnosis and treatment are not adequate to halt disease progression or provide an effective cure. DN is now considered a manifestation of inflammation where inflammatory molecules regulate most of the renal physiology. Recent advances in genetics and genomic technology have identified numerous susceptibility genes that are associated with DN, many of which have inflammatory functions. Based on their role in DN, we will discuss the current aspects of developing biomarkers and molecular therapy for advancing precision medicine.
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12
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Li A, Yi B, Han H, Yang S, Hu Z, Zheng L, Wang J, Liao Q, Zhang H. Vitamin D-VDR (vitamin D receptor) regulates defective autophagy in renal tubular epithelial cell in streptozotocin-induced diabetic mice via the AMPK pathway. Autophagy 2021; 18:877-890. [PMID: 34432556 PMCID: PMC9037529 DOI: 10.1080/15548627.2021.1962681] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in vdr knockout (vdr-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (Vdr-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or Vdr-OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in vdr-KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in vdr-KO mice and could be partially restored by paricalcitol or Vdr-OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKβ inhibition, but not by STK11/LKB1 knockout. Meanwhile, paricalcitol rescued the decreased Ca2+ concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca2+-CAMKK2-AMPK pathway in renal tubular epithelial cells. Abbreviations: ACTB/β-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKβ: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type
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Affiliation(s)
- Aimei Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hailong Han
- Centre For Medical Genetics And Hunan Key Laboratory of Medical Genetics, School Of Life Sciences, Central South University, Changsha, Hunan, China.,Department of Neuroscience, Postdoctoral Station For Basic Medicine, Hengyang School of Medicine, University of South China, Hengyang, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoxin Hu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Zheng
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianwen Wang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qin Liao
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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13
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Jiang S, Huang L, Zhang W, Zhang H. Vitamin D/VDR in Acute Kidney Injury: A Potential Therapeutic Target. Curr Med Chem 2021; 28:3865-3876. [PMID: 33213307 DOI: 10.2174/0929867327666201118155625] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/29/2020] [Accepted: 10/07/2020] [Indexed: 11/22/2022]
Abstract
Despite many strategies and parameters used in clinical practice, the incidence and mortality of acute kidney injury (AKI) are still high with poor prognosis. With the development of molecular biology, the role of vitamin D and vitamin D receptor (VDR) in AKI is drawing increasing attention. Accumulated researches have suggested that Vitamin D deficiency is a risk factor of both clinical and experimental AKI, and vitamin D/VDR could be a promising therapeutic target against AKI. However, more qualitative clinical researches are needed to provide stronger evidence for the clinical application of vitamin D and VDR agonists in the future. Issues like the route and dosage of administration also await more attention. The present review aims to summarize the current works on the role of vitamin D/VDR in AKI and provides some new insight on its therapeutic potential.
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Affiliation(s)
- Siqing Jiang
- Department of Nephrology, Third Xiangya Hospital, Central South University, 138 Tongzipo Rd, Changsha, Hunan 410013, China
| | - Lihua Huang
- Center for Medical Experiments, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Wei Zhang
- Department of Nephrology, Third Xiangya Hospital, Central South University, 138 Tongzipo Rd, Changsha, Hunan 410013, China
| | - Hao Zhang
- Department of Nephrology, Third Xiangya Hospital, Central South University, 138 Tongzipo Rd, Changsha, Hunan 410013, China
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14
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Cao Y, Yang Z, Chen Y, Jiang S, Wu Z, Ding B, Yang Y, Jin Z, Tang H. An Overview of the Posttranslational Modifications and Related Molecular Mechanisms in Diabetic Nephropathy. Front Cell Dev Biol 2021; 9:630401. [PMID: 34124032 PMCID: PMC8193943 DOI: 10.3389/fcell.2021.630401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/12/2021] [Indexed: 01/14/2023] Open
Abstract
Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by its complex pathogenesis, higher risk of mortality, and the lack of effective diagnosis and treatment methods. Many studies focus on the diagnosis and treatment of diabetes mellitus (DM) and have reported that the pathophysiology of DN is very complex, involving many molecules and abnormal cellular activities. Given the respective pivotal roles of NF-κB, Nrf2, and TGF-β in inflammation, oxidative stress, and fibrosis during DN, we first review the effect of posttranslational modifications on these vital molecules in DN. Then, we describe the relationship between these molecules and related abnormal cellular activities in DN. Finally, we discuss some potential directions for DN treatment and diagnosis. The information reviewed here may be significant in the design of further studies to identify valuable therapeutic targets for DN.
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Affiliation(s)
- Yu Cao
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
| | - Zhao Yang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhen Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Baoping Ding
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, China
| | - Haifeng Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
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15
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Zhang Q, Yang M, Xiao Y, Han Y, Yang S, Sun L. Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy. Curr Med Chem 2021; 28:1003-1024. [PMID: 31701843 DOI: 10.2174/0929867326666191108160643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.
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Affiliation(s)
- Qin Zhang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Xiao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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16
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Galuška D, Pácal L, Kaňková K. Pathophysiological Implication of Vitamin D in Diabetic Kidney Disease. Kidney Blood Press Res 2021; 46:152-161. [PMID: 33756482 DOI: 10.1159/000514286] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/24/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Vitamin D is a hormone regulating not only calcium and phosphate homeostasis but also, at the same time, exerting many other extraskeletal functions via genomic effects (gene transcription) and probably by non-genomic effects as well. Availability is ensured by dietary intake of its precursors and by de novo production via sunlight. Yet, vitamin D deficiency and insufficiency are very common across the globe and are connected to many pathophysiological states, for example, diabetes mellitus, allergies, autoimmune diseases, pregnancy complications, and recently have also been associated with worse COVID-19 clinical outcomes. SUMMARY In this review, we summarize current knowledge about vitamin D metabolism in general, its role in diabetes mellitus (mainly type 2) and diabetic complications (mainly diabetic kidney disease), and potential therapeutic perspectives including vitamin D signalling as a druggable target. Key Messages: Vitamin D is not only a vitamin but also a hormone involved in many physiological processes. Its insufficiency or deficiency can lead to many pathological states.
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Affiliation(s)
- David Galuška
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czechia,
| | - Lukáš Pácal
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Kateřina Kaňková
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czechia
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17
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Kepchia D, Currais A, Dargusch R, Finley K, Schubert D, Maher P. Geroprotective effects of Alzheimer's disease drug candidates. Aging (Albany NY) 2021; 13:3269-3289. [PMID: 33550278 PMCID: PMC7906177 DOI: 10.18632/aging.202631] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/14/2021] [Indexed: 04/18/2023]
Abstract
Geroprotectors are compounds that slow the biological aging process in model organisms and may therefore extend healthy lifespan in humans. It is hypothesized that they do so by preserving the more youthful function of multiple organ systems. However, this hypothesis has rarely been tested in any organisms besides C. elegans and D. melanogaster. To determine if two life-extending compounds for Drosophila maintain a more youthful phenotype in old mice, we asked if they had anti-aging effects in both the brain and kidney. We utilized rapidly aging senescence-accelerated SAMP8 mice to investigate age-associated protein level alterations in these organs. The test compounds were two cognition-enhancing Alzheimer's disease drug candidates, J147 and CMS121. Mice were fed the compounds in the last quadrant of their lifespan, when they have cognitive deficits and are beginning to develop CKD. Both compounds improved physiological markers for brain and kidney function. However, these two organs had distinct, tissue-specific protein level alterations that occurred with age, but in both cases, drug treatments restored a more youthful level. These data show that geroprotective AD drug candidates J147 and CMS121 prevent age-associated disease in both brain and kidney, and that their apparent mode of action in each tissue is distinct.
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Affiliation(s)
- Devin Kepchia
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Antonio Currais
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Richard Dargusch
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Kim Finley
- Donald P. Shiley BioScience Center, San Diego State University, San Diego, CA 92115, USA
| | - David Schubert
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Pamela Maher
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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18
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Song Z, Xiao C, Jia X, Luo C, Shi L, Xia R, Zhu J, Zhang S. Vitamin D/VDR Protects Against Diabetic Kidney Disease by Restoring Podocytes Autophagy. Diabetes Metab Syndr Obes 2021; 14:1681-1693. [PMID: 33889003 PMCID: PMC8057803 DOI: 10.2147/dmso.s303018] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/19/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The present study is to investigate the effect of vitamin D/Vitamin D Receptor (VDR) signaling on podocyte autophagy in diabetic nephropathy. METHODS Kidney tissue sections from patients with diabetic nephropathy and nontumor kidney were checked under electronic microscope and VDR immunohistochemistry. Diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg). Calcitriol treatment was achieved by gavage at dose of 0.1μg/kg/d. Blood, urine and kidney tissue specimens were used for serum, urine biochemistry, histopathology and molecular biology testing. Podocyte cell line MPC-5 was cultured under hyperglycaemic conditions in the absence or presence of 100 nmol/L calcitriol to investigate podocyte injury and autophagy. RESULTS VDR and autophagosomes in podocytes were significantly decreased in renal biopsy from patients with diabetic nephropathy, compared to healthy kidney tissue. Rats with STZ treatment developed typical diabetic kidney disease with low VDR expression. Calcitriol, the active form of vitamin D, could activate VDR and attenuate diabetic nephropathy including proteinuria and glomerular sclerosis. Calcitriol treatment also alleviated the podocyte foot process fusion, reduced podocyte injury marker desmin and preserved slit diaphragms proteins in diabetic nephropathy. Reduced LC3II/I, Beclin-1 and elevated p62 in renal homogenate and reduced autophagosomes and LC3II in podocytes indicated podocytes autophagy impairment in diabetic nephropathy. Whereas calcitriol treatment restored podocyte autophagy activities. In cultured podocytes, the protective effect of calcitriol against high glucose induced podocyte injury could be abated by autophagy inhibitor chloroquine. CONCLUSION Our study delivered the evidence that calcitriol/VDR signaling attenuated diabetic nephropathy and podocytes injury by restoring podocytes autophagy. This finding may have potential implication for exploring protective mechanisms of calcitriol/VDR in diabetic nephropathy.
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Affiliation(s)
- Zhixia Song
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang, Yichang, 443000, People’s Republic of China
| | - Chao Xiao
- Three Gorges University College of Medical Science, Yichang, 443000, People’s Republic of China
| | - Xiaoli Jia
- Three Gorges University College of Medical Science, Yichang, 443000, People’s Republic of China
| | - Chunhua Luo
- Department of Clinical Laboratory, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang, Yichang, 443000, People’s Republic of China
| | - Lang Shi
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang, Yichang, 443000, People’s Republic of China
| | - Rong Xia
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang, Yichang, 443000, People’s Republic of China
| | - Jiefu Zhu
- Center of Nephrology and Dialysis, Transplantation, Renmin Hospital of Wuhan University, Wuchang, Hubei, 430060, People’s Republic of China
- Correspondence: Jiefu Zhu; Shizhong Zhang Email ;
| | - Shizhong Zhang
- Three Gorges University College of Medical Science, Yichang, 443000, People’s Republic of China
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19
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Meléndez-Flores JD, Estrada-Bellmann I. Linking chronic kidney disease and Parkinson's disease: a literature review. Metab Brain Dis 2021; 36:1-12. [PMID: 32990929 DOI: 10.1007/s11011-020-00623-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 10/23/2022]
Abstract
Chronic kidney disease (CKD) has been typically implicated in cardiovascular risk, considering the function the kidney has related to blood pressure, vitamin D, red blood cell metabolism, and electrolyte and acid-base regulation. However, neurological consequences are also attributed to this disease. Among these, recent large epidemiological studies have demonstrated an increased risk for Parkinson's disease (PD) in patients with CKD. Multiple studies have evaluated individually the association of blood pressure, vitamin D, and red blood cell dysmetabolism with PD, however, no study has reviewed the potential mechanisms related to these components in context of CKD and PD. In this review, we explored the association of CKD and PD and linked the components of the former to propose potential pathways explaining a future increased risk for PD, where renin-angiotensin system, oxidative stress, and inflammation have a main role. Potential preventive and therapeutic interventions based on these associations are also explored. More preclinical studies are needed to confirm the potential link of CKD conditions and future PD risk, whereas more interventional studies targeting this association are warranted to confirm their potential benefit in PD.
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Affiliation(s)
- Jesús D Meléndez-Flores
- Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, 64700, Monterrey, NL, Mexico
- Faculty of Medicine, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Ingrid Estrada-Bellmann
- Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, 64700, Monterrey, NL, Mexico.
- Movement Disorders Clinic, Neurology Division, Internal Medicine Department, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Mexico.
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20
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Supplemental 25-hydroxycholecalciferol Alleviates Inflammation and Cardiac Fibrosis in Hens. Int J Mol Sci 2020; 21:ijms21218379. [PMID: 33171670 PMCID: PMC7664627 DOI: 10.3390/ijms21218379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022] Open
Abstract
Broiler breeder hens with efficient feed conversion rate under restricted feed intake (R-hens) or allowed unlimited access to feed (Ad-hens) progressed with cardiac functional failure and suffered early sudden death. A supplement of 69 μg 25-hydroxycholecalciferol (25-OH-D3)/kg feed improved heart health and rescued livability in both R- and Ad-hens throughout laying stage (26–60 wks). Improvements occurred through cardiac hypertrophic remodeling, reduced arrhythmias, and pathological cues. Here, we further demonstrated consistently decreased circulating and cardiac IL-6 and IL-1β levels in conjunction with reduced cardiac chemoattraction and leukocyte infiltration by 25-OH-D3 in Ad-hens and in R-hens at later time points (35 and 47 wks) (p < 0.05). Supplemental 25-OH-D3 also ameliorated cardiac fibrosis, endoplasmic reticulum (ER) stress, and autophagy, mostly in Ad-hens, as both collagen content and expression of COL3A1, as well as CCAAT box binding enhancer homologous protein (CHOP) and activating transcription factor 6 (ATF6), were consistently decreased, and suppression of microtubule-associated protein 1 light Chain 3 beta (LC3B) and Sequestosome 1 (SQSTM1) was rescued at 35 and 47 wks (p < 0.05). Vitamin D receptor-NF-κB signaling was shown to mediate these beneficial effects. The present results demonstrate that ER stress and autophagic processes along the sequence from inflammation to fibrotic changes contribute to pathological cardiac remodeling and functional compromise by Ad-feed intake. 25-OH-D3 is an effective anti-inflammatory and anti-fibrotic supplement to ameliorate cardiac pathogenesis in broiler breeder hens.
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21
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Biyashev D, Onay UV, Dalal P, Demczuk M, Evans S, Techner JM, Lu KQ. A novel treatment for skin repair using a combination of spironolactone and vitamin D3. Ann N Y Acad Sci 2020; 1480:170-182. [PMID: 32892377 PMCID: PMC7754145 DOI: 10.1111/nyas.14485] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/10/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023]
Abstract
Injury of the skin from exposure to toxic chemicals leads to the release of inflammatory mediators and the recruitment of immune cells. Nitrogen mustard (NM) and other alkylating agents cause severe cutaneous damage for which there are limited treatment options. Here, we show that combined treatment of vitamin D3 (VD3) and spironolactone (SP), a mineralocorticoid receptor antagonist, significantly improves the resolution of inflammation and accelerates wound healing after NM exposure. SP enhanced the inhibitory effect of VD3 on nuclear factor-kB activity. Combined treatment of NM-exposed mice with VD3 and SP synergistically inhibited the expression of iNOS in the skin and decreased the expression of matrix metallopeptidase-9, C-C motif chemokine ligand 2, interleukin (IL)-1α, and IL-1β. The combined treatment decreased the number of local proinflammatory M1 macrophages resulting in an increase in the M2/M1 ratio in the wound microenvironment. Apoptosis was also decreased in the skin after combined treatment. Together, this creates a proresolution state, resulting in more rapid wound closure. Combined VD3 and SP treatment is effective in modulating the immune response and activating anti-inflammatory pathways in macrophages to facilitate tissue repair. Altogether, these data demonstrate that VD3 and SP may constitute an effective treatment regimen to improve wound healing after NM or other skin chemical injury.
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Affiliation(s)
- Dauren Biyashev
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Ummiye V Onay
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Prarthana Dalal
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Michael Demczuk
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Spencer Evans
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - José-Marc Techner
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Kurt Q Lu
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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22
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Liu P, Li F, Xu X, Li S, Dong X, Chen L, Bai B, Wang Y, Qiu M, Dong Y. 1,25(OH) 2D 3 provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway. Exp Mol Pathol 2020; 114:104434. [PMID: 32240615 DOI: 10.1016/j.yexmp.2020.104434] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 03/24/2020] [Accepted: 03/28/2020] [Indexed: 12/11/2022]
Abstract
The over-activation of Toll-like receptors (TLRs) is a typical immune response to injury. Previous work has suggested that controlling the over-activation of TLR4-MyD88-NF-κB may represent a new therapeutic option for diabetic kidney disease (DKD). 1,25(OH)2D3 has also been shown to exert a protective effect on DKD, although the mechanism involved has yet to be elucidated. The aim of this study was to investigate whether 1,25(OH)2D3 protects against DKD by down-regulating the innate immune TLR-NF-κB pathway. NRK-52E cells were cultured under normal or high-glucose conditions. We then used siRNA to knock down TLR4 expression under high-glucose conditions. NRK-52E cells cultured under high-glucose conditions, and streptozotocin (STZ)-induced diabetic rats, were treated with different doses of 1,25(OH)2D3 and used as in vitro and in vivo models, respectively. Renal biochemical indicators were then measured to evaluate the influence of 1,25(OH)2D3 treatment on DKD in diabetic rats. Histological analysis was also performed to determine the extent of infiltration by inflammatory cells and tubulointerstitial fibrosis. Using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence, we determined the expression levels of TLR4, MyD88, NF-κB p65, MCP-1 and α-SMA to investigate whether 1,25(OH)2D3 could reduce the development of tubulointerstitial fibrosis. Knocking down TLR4 abolished the tubulointerstitial fibrosis caused by high-glucose conditions. High doses of 1,25(OH)2D3 consistently reduced the expression of TLR4-MyD88-NF-κB in NRK-52E cells. Moreover, high doses of 1,25(OH)2D3 had an obvious protective effect on kidney injury and inhibited the infiltration of inflammatory cells and tubulointerstitial fibrosis in diabetic rats. In conclusion, high doses of 1,25(OH)2D3 protected against tubulointerstitial fibrosis both in vitro and in vivo by downregulating the expression of TLR4-MyD88-NF-κB.
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Affiliation(s)
- Ping Liu
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Fengao Li
- Department of Endocrinology, General Hospital of Tianjin Medical University, Tianjin 300041, China
| | - Xiaoyan Xu
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Suning Li
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Xiaoying Dong
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Ling Chen
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Bin Bai
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Yarong Wang
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Mingcai Qiu
- Department of Endocrinology, General Hospital of Tianjin Medical University, Tianjin 300041, China
| | - Youping Dong
- Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
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23
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Serum Vitamin D Concentration ≥75 nmol/L Is Related to Decreased Cardiometabolic and Inflammatory Biomarkers, Metabolic Syndrome, and Diabetes; and Increased Cardiorespiratory Fitness in US Adults. Nutrients 2020; 12:nu12030730. [PMID: 32164233 PMCID: PMC7146199 DOI: 10.3390/nu12030730] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/11/2022] Open
Abstract
A serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration of ≥75 nmol/L is recommended for optimal health. We investigated the relationship between serum 25(OH)D and metabolic syndrome (MetS), diabetes, cardiometabolic biomarkers, and cardiorespiratory fitness (CRF) in US adults using clinical cut points recommended by health organizations. Data from USA's National Health and Nutrition Examination Surveys were used. Prevalences and likelihood of having MetS and diabetes according to clinical cut points for serum 25(OH)D (<30 nmol/L, 30-<50 nmol/L, 50-<75 nmo/L, and ≥75 nmol/L) were determined with multivariate logistic regression. Relations between serum 25(OH)D and various cardiometabolic biomarkers, CRF, MetS, and diabetes were tested using multivariable adjusted regression. Prevalence of MetS and diabetes were significantly lower in individuals with serum 25(OH)D ≥75 nmol/L (MetS, 21.6%; diabetes, 4.1%) compared to those with 25(OH)D <30 nmol/L (MetS, 45.5%; diabetes, 11.6%) (p < 0.0001). Individuals with serum 25(OH)D ≥75 nmol/L had significantly lower waist circumference (p < 0.0001), C-reactive protein (p = 0.003), glycated hemoglobin (p < 0.0002), fasting triglycerides (p < 0.0001), total homocysteine (p < 0.0001), and insulin resistance (p = 0.0001) and had significantly higher HDL-cholesterol (p < 0.0001) and maximal oxygen uptake (marker for CRF) (p< 0.0009) compared to those with 25(OH)D <30 nmol/L. In conclusion, serum 25(OH)D ≥75 nmol/L is associated with positive indicators related to cardiometabolic diseases in US adults.
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Solarin AU, Nourse P, Gajjar P. Vitamin D status of children with moderate to severe chronic Kidney Disease at a Tertiary Pediatric Center in Cape Town. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2020; 30:781-794. [PMID: 31464234 DOI: 10.4103/1319-2442.265453] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The prevalence of suboptimal Vitamin D levels is higher in patients with chronic kidney disease (CKD) than in the general population. Recent findings suggest that progression of CKD is linked to a suboptimal Vitamin D level. A high percentage of CKD patients have severe Vitamin D deficiency. These patients also have a low level of 25-hydroxy-vitamin D [25(OH)D] and consequently, a reduced ability to form active 1,25-dihydroxyvitamin D. Various factors underlie the low level of 25(OH)D, including a sedentary lifestyle, decreased intake of Vitamin D due to CKD-related dietary restrictions, and decreased synthesis of Vitamin D in skin due to uremia. All these factors may be particularly influential in patients with progressively worsening CKD, including those receiving chronic dialysis. The objective of our study is to determine the prevalence of Vitamin D deficiency in children with CKD stages three to five and those receiving chronic dialysis, to ascertain whether there is a relationship between Vitamin D deficiency and the stage of CKD, and to identify any clinical correlates associated with the Vitamin D status. A single-center, retrospective review was conducted of 46 children (younger than 18 years) with CKD stages 3-5D who attended the renal clinic of the Red Cross Children's Hospital between October 2013 and November 2014. In total, 73.9% of the study population had suboptimal Vitamin D levels (43.5% and 30.4% had Vitamin D deficiency and insufficiency, respectively). The prevalence of Vitamin D deficiency was significantly higher in older children (≥10 years of age) than in younger children (P = 0.000) but did not significantly differ between males and females (P = 0.693). In total, 12 of 15 black children (80%), 19 of 26 colored children (73.1%), two of four white children (50%), and one Asian child (100%) had suboptimal Vitamin D levels. Neither white nor Asian child had Vitamin D deficiency. In addition, 90% of patients undergoing chronic dialysis, 80% of whom were receiving peritoneal dialysis, had suboptimal Vitamin D levels. Age, weight, height, and the albumin concentration were significantly associated with the Vitamin D level. There was a positive linear relationship between the Vitamin D level and the serum albumin concentration (Spearman's rho correlation coefficient = 0.397, P = 0.007). In total, 87.5% of patients with nephrotic-range proteinuria had suboptimal Vitamin D levels, and 80% were Vitamin D deficient (P = 0.004). A higher percentage of Vitamin D deficiency/insufficiency cases was documented during the winter (24/34, 70.6%) than during the summer (10/34, 29.4%); however, this difference was not statistically significant (P = 0.685). Sub-optimal Vitamin D is high among children with moderate to severe CKD and significantly higher in those undergoing chronic dialysis. The emerging evidence of the role of Vitamin D in slowing progression of CKD highlights the need for monitoring and correction of Vitamin D levels in predialysis children.
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Affiliation(s)
- Adaobi Uzoamaka Solarin
- Department of Pediatrics, Lagos State University Teaching Hospital, Ikeja Lagos, Lagos, Nigeria
| | - Peter Nourse
- Department of Pediatrics and Child Health, Red Cross Children's Hospital/University of Cape Town, Cape Town, South Africa
| | - Priya Gajjar
- Department of Pediatrics and Child Health, Red Cross Children's Hospital/University of Cape Town, Cape Town, South Africa
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Donate-Correa J, Luis-Rodríguez D, Martín-Núñez E, Tagua VG, Hernández-Carballo C, Ferri C, Rodríguez-Rodríguez AE, Mora-Fernández C, Navarro-González JF. Inflammatory Targets in Diabetic Nephropathy. J Clin Med 2020; 9:458. [PMID: 32046074 PMCID: PMC7074396 DOI: 10.3390/jcm9020458] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/31/2022] Open
Abstract
One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
| | - Desirée Luis-Rodríguez
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | - Víctor G. Tagua
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
| | | | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- Escuela de Doctorado y Estudios de Posgrado, Universidad de La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | | | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (J.D.-C.); (E.M.-N.); (V.G.T.); (C.F.); (C.M.-F.)
- GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38010 San Cristóbal de La Laguna, Spain
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26
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Dhas Y, Banerjee J, Damle G, Mishra N. Serum 25(OH)D concentration and its association with inflammation and oxidative stress in the middle-aged Indian healthy and diabetic subjects. Steroids 2020; 154:108532. [PMID: 31672627 DOI: 10.1016/j.steroids.2019.108532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 10/18/2019] [Accepted: 10/24/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Vitamin D deficiency is associated with inflammation and oxidative stress. We have studied the association of 25-hydroxyvitamin D [25(OH)D] with markers of inflammation and oxidative stress. METHODS We have recruited total 180 male and female subjects aged between 30 and 50 years and divided them into two groups as control (n = 90) and T2DM (n = 90). We have measured 25(OH)D concentration, markers of inflammation including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) and markers of oxidative stress including malondialdehyde (MDA) and oxidized low-density lipoprotein (Ox-LDL) by using standard methods. RESULTS We stratified control and T2DM groups by 25(OH)D concentration and it indicates that in severe deficiency and sufficiency category IL-6, IL-1β, TNF-α, and Ox-LDL were significantly different while in moderate deficiency category only MDA was significantly different, among control and T2DM groups. In an insufficiency category, IL-6, IL-1β, TNF-α, MDA, and Ox-LDL were significantly different among control and T2DM groups. Correlation analysis indicates a negative correlation of 25(OH)D with IL-6, IL-1β, TNF-α, and Ox-LDL among total subjects. Further, logistic regression analysis demonstrated a significant association of different categories of 25(OH)D with IL-6, IL-1β, TNF-α, and Ox-LDL before and after adjustment to body mass index and waist to hip ratio. CONCLUSION This study suggest that vitamin D may have significant implications in the prevention of inflammation and oxidative stress.
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Affiliation(s)
- Yogita Dhas
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Lavale, Pune, Maharashtra 412115, India
| | - Joyita Banerjee
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Lavale, Pune, Maharashtra 412115, India
| | - Gauri Damle
- Madhunayani Diabetes Care & Eye Laser Centre, Pune, India
| | - Neetu Mishra
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Lavale, Pune, Maharashtra 412115, India.
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27
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Almeida YE, Fessel MR, do Carmo LS, Jorgetti V, Farias-Silva E, Pescatore LA, Gamarra LF, Andrade MC, Simplicio-Filho A, Mangueira CLP, Rangel ÉB, Liberman M. Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice. Sci Rep 2020; 10:87. [PMID: 31919470 PMCID: PMC6952360 DOI: 10.1038/s41598-019-55501-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus accelerates vascular calcification (VC) and increases the risk of end-stage renal disease (ESRD). Nevertheless, the impact of VC in renal disease progression in type 2 diabetes mellitus (T2DM) is poorly understood. We addressed the effect of VC and mechanisms involved in renal dysfunction in a murine model of insulin resistance and obesity (ob/ob), comparing with their healthy littermates (C57BL/6). We analyzed VC and renal function in both mouse strains after challenging them with Vitamin D3 (VitD3). Although VitD3 similarly increased serum calcium and induced bone disease in both strains, 24-hour urine volume and creatinine pronouncedly decreased only in ob/ob mice. Moreover, ob/ob increased urinary albumin/creatinine ratio (ACR), indicating kidney dysfunction. In parallel, ob/ob developed extensive intrarenal VC after VitD3. Coincidently with increased intrarenal vascular mineralization, our results demonstrated that Bone Morphogenetic Protein-2 (BMP-2) was highly expressed in these arteries exclusively in ob/ob. These data depict a greater susceptibility of ob/ob mice to develop renal disease after VitD3 in comparison to paired C57BL/6. In conclusion, this study unfolds novel mechanisms of progressive renal dysfunction in diabetes mellitus (DM) after VitD3 in vivo associated with increased intrarenal VC and highlights possible harmful effects of long-term supplementation of VitD3 in this population.
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Affiliation(s)
- Youri E Almeida
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | - Melissa R Fessel
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | | | - Vanda Jorgetti
- Department of Nephrology, Medical School, Universidade de São Paulo, São Paulo/SP, 01246000, Brazil
| | | | - Luciana Alves Pescatore
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
- Laboratório de Biologia Vascular, LIM-64, InCor, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo/SP, Brazil
| | - Lionel F Gamarra
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | | | | | | | - Érika B Rangel
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil
| | - Marcel Liberman
- Hospital Israelita Albert Einstein, São Paulo/SP, 01425001, Brazil.
- Laboratório de Biologia Vascular, LIM-64, InCor, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo/SP, Brazil.
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28
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Li S, Li W, Wu R, Yin R, Sargsyan D, Raskin I, Kong AN. Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy. AAPS JOURNAL 2019; 22:8. [PMID: 31807911 DOI: 10.1208/s12248-019-0393-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/09/2019] [Indexed: 02/06/2023]
Abstract
Moringa isothiocyanate (MIC-1) is a bioactive constituent found abundantly in Moringa oleifera which possesses antioxidant and anti-inflammation properties. However, epigenome and transcriptome effects of MIC-1 in kidney mesangial cells challenged with high glucose (HG), a pre-condition for diabetic nephropathy (DN) remain unknown. Herein, we examined the transcriptome gene expression and epigenome DNA methylation in mouse kidney mesangial cells (MES13) using next-generation sequencing (NGS) technology. After HG treatment, epigenome and transcriptome were significantly altered. More importantly, MIC-1 exposure reversed some of the changes caused by HG. Integrative analysis of RNA-Seq data identified 20 canonical pathways showing inverse correlations between HG and MIC-1. These pathways included GNRH signaling, P2Y purigenic receptor signaling pathway, calcium signaling, LPS/IL-1-mediated inhibition of RXR function, and oxidative ethanol degradation III. In terms of alteration of DNA methylation patterns, 173 differentially methylation regions (DMRs) between the HG group and low glucose (LG) group and 149 DMRs between the MIC-1 group and the HG group were found. Several HG related DMRs could be reversed by MIC-1 treatment. Integrative analysis of RNA-Seq and Methyl-Seq data yielded a subset of genes associated with HG and MIC-1, and the gene expression changes may be driven by promoter CpG status. These genes include Col4a2, Tceal3, Ret, and Agt. In summary, our study provides novel insights related to transcriptomic and epigenomic/CpG methylomic alterations in MES13 upon challenged by HG but importantly, MIC-1 treatment reverses some of the transcriptome and epigenome/CpG methylome. These results may provide potential molecular targets and therapeutic strategies for DN.
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Affiliation(s)
- Shanyi Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Wenji Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.,Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA
| | - Ilya Raskin
- Department of Plant Biology & Pathology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, 08901, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.
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29
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Li A, Zhang H, Han H, Zhang W, Yang S, Huang Z, Tan J, Yi B. LC3 promotes the nuclear translocation of the vitamin D receptor and decreases fibrogenic gene expression in proximal renal tubules. Metabolism 2019; 98:95-103. [PMID: 31226352 DOI: 10.1016/j.metabol.2019.06.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/13/2019] [Accepted: 06/14/2019] [Indexed: 01/20/2023]
Abstract
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Vitamin D receptor (VDR) belongs to the nuclear receptor superfamily and exerts a renoprotective effect through inhibiting fibrosis. Microtubule-associated protein 1 light chain 3 (LC3), a key regulator of autophagy, is abundant in the nucleus, although its primary function is in the cytoplasm. The role of nuclear LC3 and the mechanism by which LC3 shuttles between the cytoplasm and nucleoplasm has not been fully elucidated. We found that LC3 binds to VDR in an LC3-interacting region (LIR)-independent manner and promotes the nuclear translocation of VDR. Further study indicated that LC3 promotes the formation of the VDR:retinoid X receptor (RXR) heterodimer and inhibits fibrogenic genes expression in HK-2 cells induced by high glucose. Our result demonstrates that LC3 is a negative regulator of high glucose-induced fibrogenic genes expression through its ability to promote VDR signaling.
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Affiliation(s)
- Aimei Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Hailong Han
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
| | - Wei Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Shikun Yang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Zhijun Huang
- Center for Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Jieqiong Tan
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
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Omidian M, Mahmoudi M, Javanbakht MH, Eshraghian MR, Abshirini M, Daneshzad E, Hasani H, Alvandi E, Djalali M. Effects of vitamin D supplementation on circulatory YKL-40 and MCP-1 biomarkers associated with vascular diabetic complications: A randomized, placebo-controlled, double-blind clinical trial. Diabetes Metab Syndr 2019; 13:2873-2877. [PMID: 31425951 DOI: 10.1016/j.dsx.2019.07.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 07/29/2019] [Indexed: 11/26/2022]
Abstract
AIM Diabetic patients predispose to vascular diseases such as nephropathy, and retinopathy. Poor adherence to medical treatment and dietary recommendations in uncontrolled diabetes leads to vascular damages. Vitamin D has been extensively studied and found to be protective against diabetes mellitus. YKL-40 and Monocyte chemoattractant protein-1 (MCP-1) are considered to exert crucial role in diabetes and its complications. Therefore, this study was designed to investigate effects of vitamin D supplementation on serum levels of YKL-40 and MCP-1 involved in the development of diabetic complications. METHODS For 12 weeks, 48 type 2 diabetic patients enrolled in the trial and randomly were divided into two groups (n = 24 per group), receiving one of the following: 100 μg (4000 IU) vitamin D or placebo. Before and after intervention, serumYKL-40, MCP-1, insulin, IL-6, TNF-α, 25- (OH) vitamin D and HbA1c were measured. RESULTS Our results revealed that serum levels of 25 (OH) vitamin D significantly increased in vitamin D group (p < 0.001). Vitamin D supplementation also significantly reduced serum YKL-40 levels (-22.7 vs. -2.4 ng/ml; (p-value = 0.003)). There was a significant decline in MCP-1 concentration in intervention group at the end of the study (-45.7 vs. -0.9 pg/ml; (p = 0.001)). Furthermore, there was a significant decrease in IL-6, fasting insulin and HOMA-IR in intervention group after 3 months supplementation. CONCLUSIONS Daily vitamin D supplementation effectively reduced circulatory YKL-40 and MCP-1 levels in patients with type-2 diabetes and vitamin D deficiency. Vitamin D might contribute in reducing diabetic complications via modulating YKL-40 and MCP-1 signaling pathways.
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Affiliation(s)
- Mahsa Omidian
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahmoudi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Javanbakht
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Eshraghian
- Department of Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Abshirini
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Elnaz Daneshzad
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Hasani
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Alvandi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Djalali
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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Rehman MU, Rashid SM, Rasool S, Shakeel S, Ahmad B, Ahmad SB, Madkhali H, Ganaie MA, Majid S, Bhat SA. Zingerone (4-(4-hydroxy-3-methylphenyl)butan-2-one) ameliorates renal function via controlling oxidative burst and inflammation in experimental diabetic nephropathy. Arch Physiol Biochem 2019. [PMID: 29537332 DOI: 10.1080/13813455.2018.1448422] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Development of diabetic nephropathy (DN) is directly linked to oxidative stress and inflammation. In this context, inflammatory and oxidative markers have gained much attention as targets for therapeutic intervention. We studied the effect of zingerone in a streptozotocin/high fat diet (STZ/HFD)-induced type 2 diabetic Wistar rat model. Zingerone also known as vanillyl acetone is a pharmacologically active compound present usually in dry ginger. STZ/HFD caused excessive increase in ROS and inflammation in experimental animals. The treatment with zingerone markedly abrogated ROS levels, inhibited the NF-кB activation and considerably reduced level of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β), furthermore, zingerone treatment improved renal functioning by significantly decreasing the levels of kidney toxicity markers KIM-1, BUN, creatinine, and LDH and suppressed TGF-β. Collectively, these findings indicate that zingerone treatment improved renal function by anti-hyperglycaemic, anti-oxidant, and anti-inflammatory effects, suggesting the efficacy of zingerone in the treatment of DN.
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Affiliation(s)
- Muneeb U Rehman
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Shahzada Mudasir Rashid
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Saiema Rasool
- b Department of Forest ManagementForest Biotech Lab , Universiti Putra Malaysia , Serdang , Malaysia
| | - Sheeba Shakeel
- c Department of Pharmaceutical Sciences , University of Kashmir , Srinagar , India
| | - Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Sheikh Bilal Ahmad
- a Molecular Biology Lab, Division of Veterinary Biochemistry , Sheri Kashmir University of Agricultural Science & Technology (SKUAST-K) , Srinagar , India
| | - Hassan Madkhali
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Majid Ahmad Ganaie
- d Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Kingdom of Saudi Arabia
| | - Sabiya Majid
- e Department of Biochemistry , Govt. Medical College , Srinagar , India
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Gembillo G, Cernaro V, Salvo A, Siligato R, Laudani A, Buemi M, Santoro D. Role of Vitamin D Status in Diabetic Patients with Renal Disease. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:273. [PMID: 31200589 PMCID: PMC6630278 DOI: 10.3390/medicina55060273] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/03/2019] [Accepted: 06/08/2019] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM) poses a major public health problem worldwide, with ever-increasing incidence and prevalence in recent years. The Institute for Alternative Futures (IAF) expects that the total number of people with type 1 and type 2 DM in the United States will increase by 54%, from 19,629,000 to 54,913,000 people, between 2015 and 2030. Diabetic Nephropathy (DN) affects about one-third of patients with DM and currently ranks as the first cause of end-stage kidney disease in the Western world. The complexity of interactions of Vitamin D is directly related with progressive long-term changes implicated in the worsening of renal function. These changes result in a dysregulation of the vitamin D-dependent pathways. Various studies demonstrated a pivotal role of Vitamin D supplementation in regression of albuminuria and glomerulosclerosis, contrasting the increase of glomerular basement membrane thickening and podocyte effacement, with better renal and cardiovascular outcomes. The homeostasis and regulation of the nephron's function are absolutely dependent from the cross-talk between endothelium and podocytes. Even if growing evidence proves that vitamin D may have antiproteinuric, anti-inflammatory and renoprotective effects in patients with DN, it is still worth investigating these aspects with both more in vitro studies and randomized controlled trials in larger patient series and with adequate follow-up to confirm the effects of long-term vitamin D analogue supplementation in DN and to evaluate the effectiveness of this therapy and the appropriate dosage.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Antonino Salvo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Rossella Siligato
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Alfredo Laudani
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Michele Buemi
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 98,125 Messina, Italy.
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Du J, Jiang S, Hu Z, Tang S, Sun Y, He J, Li Z, Yi B, Wang J, Zhang H, Li YC. Vitamin D receptor activation protects against lipopolysaccharide-induced acute kidney injury through suppression of tubular cell apoptosis. Am J Physiol Renal Physiol 2019; 316:F1068-F1077. [PMID: 30864841 DOI: 10.1152/ajprenal.00332.2018] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI remains poorly understood. Here, we showed that vitamin D receptor (VDR) activation protects against lipopolysaccharide (LPS)-induced AKI by blocking renal tubular epithelial cell apoptosis. Mice lacking VDR developed more severe AKI than wild-type (WT) control mice after LPS treatment, which was manifested by marked increases in body weight loss and accumulation of serum blood urea nitrogen and creatinine as well as the magnitude of apoptosis of tubular epithelial cells. In the renal cortex, LPS treatment led to more dramatic downregulation of Bcl-2, more robust induction of p53-upregulated modulator of apoptosis (PUMA) and miR-155, and more severe caspase-3 activation in VDR knockout mice compared with WT control mice. Conversely, paricalcitol pretreatment markedly prevented LPS-induced AKI. Paricalcitol ameliorated body weight loss, attenuated serum blood urea nitrogen and creatinine accumulation, blocked tubular cell apoptosis, prevented the suppression of Bcl-2, and reversed PUMA and miR-155 induction and caspase-3 activation in LPS-treated WT mice. In HK2 cells, LPS induced PUMA and miR-155 by activating NF-κB, whereas 1,25(OH)2D3 blocked PUMA and miR-155 induction by repressing NF-κB activation. Both PUMA and miR-155 target Bcl-2 to promote apoptosis; namely, PUMA inhibits Bcl-2 activity, whereas miR-155 promotes Bcl-2 mRNA degradation and inhibits Bcl-2 protein translation. Collectively, these data provide strong evidence that LPS induces tubular cell apoptosis via upregulating PUMA and miR-155, whereas vitamin D/VDR signaling protects against AKI by blocking NF-κB-mediated PUMA and miR-155 upregulation.
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Affiliation(s)
- Jie Du
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
- Division of Biological Sciences, Department of Medicine, University of Chicago , Chicago, Illinois
| | - Siqing Jiang
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Zhaoxin Hu
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Shiqi Tang
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Yue Sun
- Institute of Health Sciences, China Medical University , Shenyang, Liaoning , China
| | - Jinrong He
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Zhi Li
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Bin Yi
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Jianwen Wang
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Hao Zhang
- Department of Nephrology, Third Xiangya Hospital, Central South University , Changsha, Hunan , China
| | - Yan Chun Li
- Division of Biological Sciences, Department of Medicine, University of Chicago , Chicago, Illinois
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Yang H, Xie T, Li D, Du X, Wang T, Li C, Song X, Xu L, Yi F, Liang X, Gao L, Yang X, Ma C. Tim-3 aggravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α pathway. Mol Metab 2019; 23:24-36. [PMID: 30862474 PMCID: PMC6479760 DOI: 10.1016/j.molmet.2019.02.007] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/15/2019] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
Objective Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic nephropathy (DN). However, the underlying mechanisms remain unclear. Studies suggest that T cell immunoglobulin domain and mucin domain-3 (Tim-3) has complicated roles in regulating macrophage activation, but its roles in the progression of DN are still completely unknown. Methods We downregulated Tim-3 expression in kidney (intrarenal injection of Tim-3 shRNA expressing lentivirus or global Tim-3 knockout mice) and induced DN by streptozotocin (STZ). We analyzed the degree of renal injury, especially the podocyte injury induced by activated macrophages in vitro and in vivo. Then, we transferred different bone marrow derived macrophages (BMs) into STZ-induced Tim-3 knockdown mice to examine the effects of Tim-3 on macrophages in DN. Results First, we found that Tim-3 expression on renal macrophages was increased in patients with DN and in two diabetic mouse models, i.e. STZ-induced diabetic mice and db/db mice, and positively correlated with renal dysfunction of DN patients. Tim-3 deficiency ameliorated renal damage in STZ-induced diabetes with concurrent increase in protein levels of Nephrin and WT-1. Similar effects were observed in mice with Tim-3 knockdown diabetic mice. Second, adoptive transfer of Tim-3-expressing macrophages, but not Tim-3 knockout macrophages, accelerated diabetic renal injury in DN mice, suggesting a key role for Tim-3 on macrophages in the development of DN. Furthermore, we found NF-κB activation and TNF-α excretion were upregulated by Tim-3 in diabetic kidneys, and podocyte injury was associated with the Tim-3-mediated activation of the NF-κB/TNF-α signaling pathway in DN macrophages both in vivo and in vitro. Conclusions These results suggest that Tim-3 functions as a key regulator in renal inflammatory processes and serves as a potential therapeutic target for renal injury in DN.
Tim-3 aggravates the progression of diabetic nephropathy (DN) by triggering the NF-κB/TNF-α pathway in renal macrophages. Tim-3 highly expresses on renal macrophages has positive correlation with bad renal function of DN patients. Tim-3 expressed on macrophages accelerates podocyte injury in vitro and in vivo. Tim-3 functions as a key regulator in renal inflammatory processes and serves as a potential therapeutic target in DN.
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Affiliation(s)
- Huimin Yang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China; Department of Nephropathy, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Tingting Xie
- Department of Nephropathy, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Dengren Li
- Department of Nephropathy, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Xianhong Du
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Leiqi Xu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Fan Yi
- Department of Pharmacology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China
| | - Xiangdong Yang
- Department of Nephropathy, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, PR China.
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Hu X, Liu W, Yan Y, Liu H, Huang Q, Xiao Y, Gong Z, Du J. Vitamin D protects against diabetic nephropathy: Evidence-based effectiveness and mechanism. Eur J Pharmacol 2019; 845:91-98. [PMID: 30287151 DOI: 10.1016/j.ejphar.2018.09.037] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/06/2018] [Accepted: 09/27/2018] [Indexed: 02/08/2023]
Abstract
Vitamin D has been suggested to harbor multiple biological activities, among them the potential of vitamin D in the protection of diabetic nephropathy (DN) has attracted special attention. Both animal studies and clinical trials have documented an inverse correlation between low vitamin D levels and DN risk, and supplementation with vitamin D or its active derivatives has been demonstrated to improve endothelial cell injury, reduce proteinuria, attenuate renal fibrosis, and resultantly retard DN progression. Vitamin D exerts its pharmacological effects primarily via vitamin D receptor, whose activation inhibits the renin-angiotensin system, a key culprit for DN under hyperglycemia. The anti-DN benefit of vitamin D can be enhanced when administrated in combination with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Mechanistic studies reveal that pathways relevant to inflammation participate in the pathogenesis of DN, however, consumption of vitamin D-related products negatively regulates inflammatory response at multiple levels, indicated by inhibiting macrophage infiltration, nuclear factor-kappa B (NF-κB) activation, and production of such inflammatory mediators as transforming growth factor-β(TGF-β), monocyte chemoattractant protein 1(MCP-1), and regulated upon activation normal T cell expressed and secreted protein(RANTES). The robust anti-inflammatory property of vitamin D-related products allows them with a promising renoprotective therapeutic option for DN. This review summarizes new advances in our understanding of vitamin D-related products in the DN management.
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Affiliation(s)
- Xiaofang Hu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Wanli Liu
- National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; Department of Nursing, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Hengdao Liu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 410013, Henan, China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yi Xiao
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Zhicheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
| | - Jie Du
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
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Mohammed MA, Aboulhoda BE, Mahmoud RH. Vitamin D attenuates gentamicin-induced acute renal damage via prevention of oxidative stress and DNA damage. Hum Exp Toxicol 2018; 38:321-335. [DOI: 10.1177/0960327118812166] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background: Despite being one of the most nephrotoxic drugs, gentamicin (GM) remains a mainstay as a first-choice agent in a vast variety of clinical situations owing to its superlative efficiency as a broad-spectrum antibiotic in treating several life-threatening bacterial infections. This urgently calls for the need for in-depth analysis of the mechanisms governing GM-induced nephrotoxicity and entails the necessity of presenting novel protective agents capable of ameliorating those renal deleterious effects. The reactive oxygen species and redox-sensitive transcription factors in GM-induced nephrotoxicity have recently called attention. Purpose: This study has been designed to shed light on the possible mechanisms of GM-induced nephrotoxicity and to provide a consensus set of histopathological, immunohistochemical, genetic and biochemical parameters elucidating the protective role of vitamin D against this nephrotoxicity. Methods: Twenty-four adult male albino rats were equally divided into four groups: group I (control group), group II (GM), group III (GM + vitamin D) and group IV (vitamin D only). Kidney function tests, histopathological examination, gene expression of nuclear factor 2, nuclear factor kappa beta (NF-κB) and western blot of NF-κB p65, assessment of glutathione peroxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase by ELISA, as well as immunohistochemical evaluation of inducible nitric oxide, malondialdehyde, 8-hydroxy 2 deoxyguanine and vitamin D receptor, have been carried out. Results: The kidney function deterioration, tissue oxidative stress development and the histopathological changes induced by GM were significantly attenuated by vitamin D administration. Conclusion: Vitamin D attenuates GM nephrotoxicity through its antioxidant properties and prevention of DNA damage.
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Affiliation(s)
- MA Mohammed
- Department of Physiology, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
| | - BE Aboulhoda
- Department of Anatomy, Faculty of Medicine, Cairo University, Giza, Egypt
| | - RH Mahmoud
- Department of Biochemistry, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Xie Z, Zhong L, Wu Y, Wan X, Yang H, Xu X, Li P. Carnosic acid improves diabetic nephropathy by activating Nrf2/ARE and inhibition of NF-κB pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 47:161-173. [PMID: 30166101 DOI: 10.1016/j.phymed.2018.04.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/22/2018] [Accepted: 04/15/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN), one of the most serious complications of diabetes, is the leading cause of morbidity and mortality of end-stage renal disease. Our previous research found that carnosic acid (CA) or rosemary extract can effectively improve glucose and lipid metabolism disorder by inhibiting SREBPs. PURPOSE In this study, we aimed to explore the therapeutic effects of CA on the DN. METHODS The mice glomerular mesangial cells (mGMCs) were used to evaluate the anti-oxidative and anti-inflammation effects of CA under high glucose (HG) condition. Furthermore, db/db mice and streptozotocin (STZ)-induced diabetic mice were used to investigate the effects of CA against DN in vivo. RESULTS The results showed that CA activated Nrf2, inhibited NF-κB pathway and regulated related downstream genes in mGMC under HG condition. A 14-week treatment of mice with CA reduced water uptake and urine volume, attenuated diabetes-induced albuminuria, increased urine creatinine, and subsequently improved the glomerular sclerosis and mesangial expansion in db/db mice. Similarly, a 20-week oral administration of CA improved kidney damage in STZ-induced diabetic mice. In addition, CA inhibited the expression of profibrotic factors, such as TGF-β1, fibronectin and E-cadherin. Compared to irbesartan, CA exerted better glucose lowering effect, and in kidney, CA was more potent to reduce fibronectin and E-cadherin expression. In all the animal experiment, CA did not lead to abnormal damages to other tissues. CONCLUSION These findings suggest that CA is a safe compound which exerts the protective effects on diabetes-induced kidney complications.
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Affiliation(s)
- Zhisheng Xie
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Lingjun Zhong
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yanrao Wu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaomeng Wan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Hua Yang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaojun Xu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
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Abstract
Inflammation and reactive oxygen species (ROS) play crucial roles in the progression of chronic kidney diseases. Vitamin D has been shown anti-inflammatory effects, but the underlying mechanism is not fully understood. Here, we investigated whether calcitriol exerts protective effects via upregulating A20 in angiotensinII (AngII)-induced renal injury. Male C57BL/6 mice were infused with vehicle or AngII for 10 days. Calcitriol reduced infiltration of T lymphocytes and macrophages. This reduction of inflammatory cells was accompanied by elevated A20 and decreased pro-inflammatory cytokines (PICs) and reactive oxygen species (ROS). Calcitriol could inhibit NF-κB activation and necroptotic pathway. Induction of A20 was located primarily to the tubular epithelial cells. In rat proximal tubular epithelial cells (NRK-52E), calcitriol stably upregulated A20 and reduced the PICs and ROS. Inhibitory effect of A20 on PICs and ROS depended on suppressing NF-κB pathway and necroptotic pathway, respectively. A20 knockdown diminished the effect of calcitriol on suppressing NF-κB and necroptotic pathways. However, A20 deficiency could not abrogate the inhibitory effect of calcitriol on NF-κB and necroptotic pathways. Our results established that A20 is involved in the renoprotective effect by calcitriol via negatively modulating the NF-κB pathway and necroptotic pathway in AngII-induced renal injury.
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Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone. Eur J Pharmacol 2018; 831:68-76. [PMID: 29715453 DOI: 10.1016/j.ejphar.2018.04.032] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/07/2018] [Accepted: 04/26/2018] [Indexed: 12/11/2022]
Abstract
Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/β-catenin signaling, p-S536NF-κBp65, PPARγ, Ang II/TGF-β, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/β-catenin and pS536-NF-κBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-κBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARγ and TGF-β, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the β-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-κB, Ang II, ACE2, TGFβ, and a modulation of Wnt4/β-catenin pathway.
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Angelbello AJ, Chen JL, Childs-Disney JL, Zhang P, Wang ZF, Disney MD. Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Chem Rev 2018; 118:1599-1663. [PMID: 29322778 DOI: 10.1021/acs.chemrev.7b00504] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been converted into chemical probes of function, preclinical lead modalities, and ultimately U.S. Food and Drug Administration (FDA)-approved drugs. In particular, we focus on the use of oligonucleotide-based modalities to target disease-causing RNAs; small molecules that target DNA, RNA, or protein; the rational repurposing of known therapeutic modalities; and the advantages of pharmacogenetics. Lastly, we discuss the remaining challenges and opportunities in the direct utilization of genome sequence to enable design of medicines.
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Affiliation(s)
- Alicia J Angelbello
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Jonathan L Chen
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Jessica L Childs-Disney
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Peiyuan Zhang
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Zi-Fu Wang
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Matthew D Disney
- Departments of Chemistry and Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States
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Yang S, Li A, Wang J, Liu J, Han Y, Zhang W, Li YC, Zhang H. Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases. Curr Med Chem 2018; 25:3256-3271. [PMID: 29446731 PMCID: PMC6142412 DOI: 10.2174/0929867325666180214122352] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/25/2018] [Accepted: 02/08/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Kidney disease is a serious problem that adversely affects human health, but critical knowledge is lacking on how to effectively treat established chronic kidney disease. Mounting evidence from animal and clinical studies has suggested that Vitamin D Receptor (VDR) activation has beneficial effects on various renal diseases. METHODS A structured search of published research literature regarding VDR structure and function, VDR in various renal diseases (e.g., IgA nephropathy, idiopathic nephrotic syndrome, renal cell carcinoma, diabetic nephropathy, lupus nephritis) and therapies targeting VDR was performed for several databases. RESULT Included in this study are the results from 177 published research articles. Evidence from these papers indicates that VDR activation is involved in the protection against renal injury in kidney diseases by a variety of mechanisms, including suppression of RAS activation, anti-inflammation, inhibiting renal fibrogenesis, restoring mitochondrial function, suppression of autoimmunity and renal cell apoptosis. CONCLUSION VDR offers an attractive druggable target for renal diseases. Increasing our understanding of VDR in the kidney is a fertile area of research and may provide effective weapons in the fight against kidney diseases.
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Affiliation(s)
| | | | | | | | | | | | | | - Hao Zhang
- Address correspondence to this author is at the Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Tel: 86-731-88638238; E-mail:
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Suryavanshi SV, Kulkarni YA. NF-κβ: A Potential Target in the Management of Vascular Complications of Diabetes. Front Pharmacol 2017; 8:798. [PMID: 29163178 PMCID: PMC5681994 DOI: 10.3389/fphar.2017.00798] [Citation(s) in RCA: 271] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023] Open
Abstract
Diabetes is a metabolic disorder affecting large percentage of population worldwide. NF-κβ plays key role in pathogenesis of vascular complications of diabetes. Persistent hyperglycemia activates NF-κβ that triggers expression of various cytokines, chemokines and cell adhesion molecules. Over-expression of TNF-α, interleukins, TGF-β, Bcl2 and other pro-inflammatory proteins and pro-apoptotic genes by NF-κβ is key risk factor in vascular dysfunction. NF-κβ over-expression also triggers calcification of endothelial cells leading to endothelial dysfunction and further vascular complications. Inhibition of NF-κβ pro-inflammatory pathway is upcoming novel target for management of vascular complications of diabetes. Various natural and synthetic inhibitors of NF-κβ have been studied in management of diabetic complications. Recent preclinical and clinical studies validate NF-κβ as promising target in the management of vascular complications of diabetes.
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Affiliation(s)
- Sachin V Suryavanshi
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's Narsee Monjee Institute of Management Studies, Mumbai, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's Narsee Monjee Institute of Management Studies, Mumbai, India
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Hernández-Sánchez F, Guzmán-Beltrán S, Herrera MT, Gonzalez Y, Salgado M, Fabian G, Torres M. High glucose induces O-GlcNAc glycosylation of the vitamin D receptor (VDR) in THP1 cells and in human macrophages derived from monocytes. Cell Biol Int 2017; 41:1065-1074. [PMID: 28710799 DOI: 10.1002/cbin.10827] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 07/13/2017] [Indexed: 01/13/2023]
Abstract
Chronic hyperglycemia increases the carbon flux through the hexosamine pathway, allowing the accumulation of UDP-GlcNAc. UDP-GlcNAc is the sugar donor for the enzyme-mediated protein glycosylation event known as OGlcNAcylation. This posttranslational modification targets several transcription factors implicated in glucose toxicity, insulin resistance, and diabetes. Vitamin D plays an important role in glucose homeostasis and insulin secretion through transcriptional mechanisms mediated by its receptor (VDR). Vitamin D deficiency has been associated with higher susceptibility to bacterial diseases in diabetic patients. However, it has not been explored whether VDR is subject to OGlcNAcylation or whether high glucose affects its transcriptional or biological activities. The aim of this study was to evaluate the effect of hyperglycemia on VDR OGlcNAcylation and its effects on vitamin D-mediated transcription. We predicted potential OGlcNAcylation sites using free software. Our results showed that hyperglycemia (30 mM) induces the OGlcNAcylation of VDR in THP1 cells and in human macrophages derived from monocytes (MDM). This condition did not hamper the vitamin D-dependent activation of LL-37 gene expression, and even did not impair the macrophage bactericidal activity. Our study provides new insight into vitamin D receptor posttranslational modification that may have relevance on the physiological responses of long-term hyperglycemia.
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Affiliation(s)
- Fernando Hernández-Sánchez
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - Silvia Guzmán-Beltrán
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - María Teresa Herrera
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - Yolanda Gonzalez
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - Manuel Salgado
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - Guadalupe Fabian
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
| | - Martha Torres
- Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, México City, Mexico, 1408
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Trohatou O, Tsilibary EF, Charonis A, Iatrou C, Drossopoulou G. Vitamin D3 ameliorates podocyte injury through the nephrin signalling pathway. J Cell Mol Med 2017; 21:2599-2609. [PMID: 28664547 PMCID: PMC5618699 DOI: 10.1111/jcmm.13180] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/24/2017] [Indexed: 12/19/2022] Open
Abstract
Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D3 through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25‐dihydroxyvitamin D3 analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25‐dihydroxyvitamin D3 (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ)‐diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose‐mediated down‐regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose‐induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co‐localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down‐regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ‐diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN.
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Affiliation(s)
- Ourania Trohatou
- Institute of Biosciences and Applications, NCSR 'Demokritos', Athens, Greece
| | | | - Aristidis Charonis
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece
| | - Christos Iatrou
- Center for Nephrology, G. Papadakis General Hospital of Nikea-Pireaus, Athens, Greece
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Zhang M, Wang S, Pan Z, Ou T, Ma J, Liu H, Li R, Yang P, Han W, Guan S, Hou X, Fang W, Qu X. AMPK/NF-κB signaling pathway regulated by ghrelin participates in the regulation of HUVEC and THP1 Inflammation. Mol Cell Biochem 2017; 437:45-53. [DOI: 10.1007/s11010-017-3094-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/08/2017] [Indexed: 12/18/2022]
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Abo El Gheit R, Emam MN. Targeting heme oxygenase-1 in early diabetic nephropathy in streptozotocin-induced diabetic rats. Physiol Int 2017; 103:413-427. [PMID: 28229631 DOI: 10.1556/2060.103.2016.4.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Diabetic nephropathy (DN) is one of the most common microvascular diabetic complications. This study was designed to evaluate the possible protective effect and underlying mechanisms of HO-1 induction in streptozotocin (STZ)-induced early DN in rats. The diabetic rats were divided into three groups: STZ-diabetic, cobalt protoporphyrin (CoPP)-treated diabetic, and zinc protoporphyrin IX (ZnPP)-treated diabetic groups. Compared to the STZ-diabetic group, CoPP-induced HO-1 upregulation improved the diabetic state and renal functional parameters, suppressed the renal proinflammatory marker, NF-κB, abrogated the elevated renal hydroxyprolin, and decreased the enhanced renal nicotinamide adenine dinucleotide phosphate oxidase activity with parallel reduction of urinary oxidative stress markers. On the contrary, treatment with ZnPP abrogated HO-1 levels, aggravated the diabetic condition with further increases in renal oxidative stress, fibrotic and inflammatory markers, and exacerbated renal dysfunction in diabetic animals. These findings suggest that the reduced diabetic renal injury upon HO-1 induction implicates the role of HO-1 induction as a potential treatment for DN.
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Affiliation(s)
- R Abo El Gheit
- 1 Physiology Department, Faculty of Medicine, Tanta University , Tanta, Egypt
| | - M N Emam
- 1 Physiology Department, Faculty of Medicine, Tanta University , Tanta, Egypt
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Effect of paricalcitol on pancreatic oxidative stress, inflammatory markers, and glycemic status in diabetic rats. Ir J Med Sci 2017; 187:75-84. [PMID: 28551720 DOI: 10.1007/s11845-017-1635-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/18/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVES This study is designed to explore the effect of paricalcitol (vitamin D receptor agonist) on pancreatic oxidative stress, inflammatory markers, and adiponectin and glycemic status in diabetic rats. MATERIALS AND METHODS Forty Sprague-Dawley male rats aged 10-12 weeks (150-250 g) were used in this study. Type 2 diabetes was developed by providing 4 weeks of high-fat-diet feeding before one shot of streptozotocin injection (40 mg/kg i.p.). Four study groups were designed as normal control rats, diabetic control vehicle-treated, diabetic paricalcitol-treated (0.8 μg/kg), and diabetic glibenclamide-treated (0.6 mg/kg) groups with 10 animals in each. After treatment of diabetic rats for 3 months, pancreatic inflammatory and oxidative stress markers, plasma adiponectin, glycemic status parameters, and histopathological pancreatic islet changes were evaluated. RESULTS Paricalcitol and glibenclamide treatment significantly (P < 0.05) decreased plasma glucose, insulin resistance, and pancreatic malondialdehyde and tumor necrosis factor-α levels. Moreover, they significantly (P < 0.05) increased plasma fasting insulin, C-peptide, adiponectin, pancreatic IL-2, catalase, superoxide dismutase, glutathione peroxidase, and reduced glutathione when contrasted with diabetic control rats. Furthermore, they prevented extensive histopathological damage in the pancreas of diabetic rats. CONCLUSIONS Paricalcitol reduced pancreatic oxidative stress and inflammatory markers, and improved glycemic status in diabetic rats.
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Chung S, Kim M, Koh ES, Hwang HS, Chang YK, Park CW, Kim SY, Chang YS, Hong YA. Serum 1,25-dihydroxyvitamin D Better Reflects Renal Parameters Than 25-hydoxyvitamin D in Patients with Glomerular Diseases. Int J Med Sci 2017; 14:1080-1087. [PMID: 29104461 PMCID: PMC5666538 DOI: 10.7150/ijms.20452] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/24/2017] [Indexed: 01/21/2023] Open
Abstract
Background: Impaired vitamin D metabolism may contribute to the development and progression of chronic kidney disease. The purpose of this study was to determine associations of circulating vitamin D with the degree of proteinuria and estimated glomerular filtration rate (eGFR) in patients with biopsy-proven glomerular diseases. Methods: Clinical and biochemical data including blood samples for 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were collected from patients at the time of kidney biopsy. Results: Serum 25(OH)D levels were not different according to eGFR. However, renal function was significantly decreased with lower serum 1,25(OH)2D levels (P < 0.001). The proportions of nephrotic-range proteinuria and renal dysfunction (eGFR ≤ 60 mL/min/1.73 m2) progressively increased with declining 1,25(OH)2D but not 25(OH)D. Multivariable linear regression analysis showed that 25(OH)D was significantly correlated with serum albumin and total cholesterol (β = 0.224, P = 0.006; β = -0.263, P = 0.001) and 1,25(OH)2D was significantly correlated with eGFR, serum albumin and phosphorus (β = 0.202, P = 0.005; β = 0.304, P < 0.001; β = -0.161, P = 0.024). In adjusted multivariable linear regression, eGFR and 24hr proteinuria were independently correlated only with 1,25(OH)2D (β = 0.154, P = 0.018; β = -0.171, P = 0.012), but not 25(OH)D. The lower level of 1,25(OH)2D was associated with the frequent use of immunosuppressive agents (P < 0.001). Conclusion: It is noteworthy in these results that circulating 1,25(OH)2D may be superior to 25(OH)D as a marker of severity of glomerular diseases.
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Affiliation(s)
- Sungjin Chung
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Minyoung Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sil Koh
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyeon Seok Hwang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Kyung Chang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Suk Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Sik Chang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu Ah Hong
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Yi B, Huang J, Zhang W, Li AM, Yang SK, Sun J, Wang JW, Li YC, Zhang H. Vitamin D Receptor Down-Regulation Is Associated With Severity of Albuminuria in Type 2 Diabetes Patients. J Clin Endocrinol Metab 2016; 101:4395-4404. [PMID: 27552538 DOI: 10.1210/jc.2016-1516] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CONTEXT Inflammation plays an important role in albuminuria in type 2 diabetes mellitus (T2DM). The vitamin D receptor (VDR) has potent anti-inflammatory activities. OBJECTIVE To investigate the correlation between VDR expression and albuminuria in T2DM. DESIGN/SETTING/PATIENTS Renal biopsies from T2DM patients with albuminuria (n = 8) and nondiabetic subjects (n = 4) were compared for VDR expression by immunohistochemistry. Recruited T2DM patients (n = 242; estimated glomerular filtration rate > 60 mL/min/1.73 m2) were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g; n = 85), microalbuminuria (30 mg/g ≤ uACR < 300 mg/g; n = 84), and macroalbuminuria (uACR ≥ 300 mg/g; n = 73), with healthy individuals (n = 72) as controls. Peripheral blood mononuclear cells (PBMCs) from these subjects were analyzed for VDR mRNA (n = 314), TNF-α mRNA (n = 314), microRNA (miR)-346 (n = 120; 30 for each group), and VDR protein (n = 80; 20 for each group). PBMCs from randomly selected subjects (n = 6 for each group) were cultured ex vivo to evaluate the effect of TNF-α on miR-346 and VDR, and miR-346-mediated VDR suppression was further explored in HK2 cells. RESULTS VDR expression was down-regulated in PBMCs and renal tubular epithelial cells from T2DM patients with albuminuria. VDR mRNA and protein levels were both negatively correlated with uACR, and VDR mRNA was inversely correlated with TNF-α and miR-346 in PBMCs from T2DM patients. TNF-α reduced VDR while inducing miR-346 in cultured PBMCs. TNF-α suppressed VDR by up-regulating miR-346 in HK2 cells. CONCLUSIONS VDR down-regulation in PBMCs is independently associated with the severity of albuminuria in T2DM. TNF-α suppression of VDR in PBMCs and HK2 cells is mediated by miR-346.
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Affiliation(s)
- Bin Yi
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Jing Huang
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Wei Zhang
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Ai Mei Li
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Shi Kun Yang
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Jian Sun
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Jian Wen Wang
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Yan Chun Li
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
| | - Hao Zhang
- Department of Nephrology (B.Y., J.H., W.Z., A.M.L., S.K.Y., J.S., J.W.W., H.Z.), The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; and Department of Medicine (Y.C.L.), Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637
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Wang H, Wang J, Qu H, Wei H, Ji B, Yang Z, Wu J, He Q, Luo Y, Liu D, Duan Y, Liu F, Deng H. In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D 3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway. Endocrine 2016; 54:348-359. [PMID: 27395420 DOI: 10.1007/s12020-016-0999-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/24/2016] [Indexed: 02/07/2023]
Abstract
We investigated whether 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) could improve early diabetic nephropathy through the DNA-damage-inducible transcript 4/tuberous sclerosis 2/mammalian target of rapamycin pathway. Rat mesangial cells were cultured in media containing normal glucose or high glucose and were treated with or without 1,25(OH)2D3. Mesangial cells proliferation was measured. Streptozotocin-induced diabetic rats were injected intravenously with a recombinant lentivirus against the rat vitamin D receptor gene. Urinary and serum albumin, fasting plasma glucose, serum triglyceride, total cholesterol, calcium, parathyroid hormone and serum 25-dihydroxy-vitamin D (25(OH)D) levels, mean glomerular volume, glomerular basement membrane thickness and total kidney volume were determined. The expressions of vitamin D receptor, DNA-damage-inducible transcript 4, and mammalian target of rapamycin were measured. 1,25(OH)2D3 inhibited the proliferation of mesangial cells induced by hyperglycemia. 1,25(OH)2D3 also significantly reduced albumin excretion, mean glomerular volume, glomerular basement membrane, and total kidney volume in rats with diabetic nephropathy. The expression of DNA-damage-inducible transcript 4 was elevated by 1,25(OH)2D3 treatment. The phosphorylation of mammalian target of rapamycin was reduced by 1,25(OH)2D3 treatment. Vitamin D receptor gene silencing blocked all of the above results. The current study demonstrates that 1,25(OH)2D3 can effectively inhibit mesangial cells proliferation induced by hyperglycemia, thus suppressing the development of diabetic nephropathy. This study also shows that the nephron-protective effect of 1,25(OH)2D3 occurs partly through the DDIT4/TSC2/mTOR pathway.
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Affiliation(s)
- Hang Wang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Jianmin Wang
- Department of Nephrology, Chongqing Armed Corps Police Hospital, Chongqing, P.R. China
| | - Hua Qu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Huili Wei
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Baolan Ji
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Zesong Yang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Jing Wu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Qin He
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Yuanyuan Luo
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Dan Liu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Yang Duan
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Fang Liu
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Huacong Deng
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
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