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Kennedy C, Doyle R, Gough O, Mcevoy C, McAnallen S, Hughes M, Sheng X, Crifo B, Andrews D, Gaffney A, Rodriguez J, Kennedy S, Dillon E, Crean D, Zhang W, Yi Z, Nair V, Susztak K, Hirschhorn J, Florez J, Groop PH, Sandholm N, Kretzler M, McKay GJ, McKnight AJ, Maxwell AP, Matallanas D, Dorman A, Martin F, Conlon PJ, Sadlier DM, Brennan E, Godson C. A Novel Role for FERM Domain-Containing Protein 3 in CKD. KIDNEY360 2024; 5:1799-1812. [PMID: 39450948 PMCID: PMC11687992 DOI: 10.34067/kid.0000000602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024]
Abstract
Key Points We have identified a transcriptional signature of 93 genes associated with CKD severity and progression. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 gene expression is reduced in the context of more severe kidney disease and in individuals who go on to develop progressive disease. Protein 4.1, ezrin, radixin, moesin domain-containing protein 3 interacts with proteins of the cell cytoskeleton and cell-cell junctions in proximal tubule epithelial cells. Background Currently, there are limited methods to link disease severity and risk of disease progression in CKD. To better understand this potential relationship, we interrogated the renal transcriptomic profile of individuals with CKD with measures of CKD severity and identified protein 4.1, ezrin, radixin, moesin-domain containing protein 3 (FRMD3 ) as a candidate gene for follow-up study. Methods RNA-sequencing was used to profile the transcriptome of CKD biopsies from the North Dublin Renal BioBank, the results of which were correlated with clinical parameters. The potential function of FRMD3 was explored by interrogating the FRMD3 interactome and assessing the effect of lentiviral mediated FRMD3 knock down on human renal proximal tubule epithelial cells by assessing cell viability, metabolic activity, and structural markers. Results We identified a subset of 93 genes which are significantly correlated with eGFR and percentage tubulointerstitial fibrosis at time of biopsy and with CKD progression 5 years postbiopsy. These results were validated against transcriptomic data from an external cohort of 432 nephrectomy samples. One of the top-ranking genes from this subset, FRMD3, has previously been associated with the risk of developing diabetic kidney disease. Interrogating the interactome of FRMD3 in tubule epithelial cells revealed interactions with cytoskeletal components of cell-cell junctions. Knockdown of FRMD3 expression in tubule epithelial cells resulted in increased proapoptotic activity within the cells, as well as dysregulation of E-Cadherin. Conclusions We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this, we have identified a possible role for FRMD3 in tubule cell structure and health.
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Affiliation(s)
- Ciarán Kennedy
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Ross Doyle
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
- School of Medicine, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
| | - Oisin Gough
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Caitriona Mcevoy
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
- Tallaght University Hospital, Dublin; and Trinity Kidney Centre, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Susan McAnallen
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Maria Hughes
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Xin Sheng
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China
| | - Bianca Crifo
- School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Darrell Andrews
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Andrew Gaffney
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Javier Rodriguez
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Susan Kennedy
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
- TriviumVet, Waterford, Ireland
| | - Eugene Dillon
- UCD Conway Institute Core Technologies, University College Dublin, Dublin, Ireland
| | - Daniel Crean
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
- School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - Weijia Zhang
- Icahn School of Medicine at Mount Sinai, New York, New York
| | - Zhengzi Yi
- Icahn School of Medicine at Mount Sinai, New York, New York
| | - Viji Nair
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Katalin Susztak
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joel Hirschhorn
- Endocrine Division and Diabetes Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jose Florez
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Matthias Kretzler
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Gareth J. McKay
- Centre for Public Health, Queens University of Belfast, Northern Ireland, United Kingdom
| | - Amy Jayne McKnight
- Centre for Public Health, Queens University of Belfast, Northern Ireland, United Kingdom
| | - Alexander P. Maxwell
- Centre for Public Health, Queens University of Belfast, Northern Ireland, United Kingdom
| | - David Matallanas
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Anthony Dorman
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | - Finian Martin
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Peter J. Conlon
- National Kidney Transplant Service, Department of Nephrology and Kidney Transplantation, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Denise M. Sadlier
- School of Medicine, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
| | - Eoin Brennan
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, UCD School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
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Røikjer J, Borbjerg MK, Andresen T, Giordano R, Hviid CVB, Mørch CD, Karlsson P, Klonoff DC, Arendt-Nielsen L, Ejskjaer N. Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods. J Diabetes Sci Technol 2024:19322968241279553. [PMID: 39282925 PMCID: PMC11571639 DOI: 10.1177/19322968241279553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.
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Affiliation(s)
- Johan Røikjer
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Mette Krabsmark Borbjerg
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
| | - Trine Andresen
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Rocco Giordano
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Claus Vinter Bødker Hviid
- Department of Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Carsten Dahl Mørch
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Pall Karlsson
- Danish Pain Research Center, Aarhus University, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | | | - Lars Arendt-Nielsen
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
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Wu S, Yi B, Dai Y, Liao X, Peng J, Li A. Correlation between polymorphisms of SIRT2 gene and renal injury in patients with type 2 diabetes mellitus. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:1005-1014. [PMID: 39788488 PMCID: PMC11495987 DOI: 10.11817/j.issn.1672-7347.2024.240186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Indexed: 01/12/2025]
Abstract
OBJECTIVES Genetic factors play an important role in the pathogenesis of diabetic kidney disease (DKD). Studies have shown that SIRT2 gene polymorphism is associated with the pathogenesis of type 2 diabetes mellitus (T2DM), but its role in DKD remains unclear. This study aims to analyze the distribution of alleles and genotypes of SIRT2 gene in patients with T2DM, and investigate the association between SIRT2 genetic polymorphism and DKD susceptibility in T2DM patients, which may provide new ideas for the pathogenesis of DKD. METHODS A toal of 205 T2DM patients who receiving treatment in the Third Xiangya Hospital of Central South University were divided into a DKD group (n=100) and a DM group (n=105) according to the presence of kidney injury, and 100 healthy volunteers were selected as NC group. Clinical data of the subjects were collected and estimated glomerular filtration rate (eGFR) were calculated. Genomic DNA was extracted and the genotypes of single nucleotide polymorphism (SNP) loci (rs11879029, rs11879010, and rs2241703) were determined using Sanger chain termination method. The genotype/allele frequencies among the 3 groups were compared. Logistic regression was used to analyze the correlation between SNP locus genotype of SIRT2 gene and risk of DKD in T2DM patients. According to the genotypes of rs11879029/rs11879010, T2DM patients were divided into a GG1/GG2 group, a GA1/GA2 group, and an AA1/AA2 group, and the clinical data were compared. Linkage disequilibrium analysis and haplotype analysis were performed. RESULTS The genotype distribution and allele frequencies of the rs11879029 and rs11879010 loci in the DKD group were significantly different in comparison with the NC and DM groups (all P<0.05). For rs2241703, there were no differences in genotype and allele frequencies (all P>0.05). After correcting by age, gender, systolic blood pressure, duration of diabetes, glycosylated hemoglobin, and serum albumin, rs11879029 and rs11879010 genotype were associated with DKD susceptibility in T2DM patients. Carriers of rs11879029 genotype AA were 6.27 times more likely to have DKD than carriers of genotype GG. And carriers of rs11879010 genotype AA were 4.72 times more likely to have DKD than carriers of genotype GG. The eGFR levels in the AA1/AA2 groups were significantly lower than those in the GG1/GG2 groups (both P<0.05). Analysis of linkage disequilibrium showed complete linkage disequilibrium existed between SIRT2 rs11879029 and rs11879010, and the 2 SNPs (rs11879029 and rs11879010) were in strong linkage disequilibrium with rs2241703. Monotype GGG reduced the risk of DKD in T2DM patients (OR=0.53, 95% CI 0.35 to 0.81, P=0.003), while haplotype AAG increased the risk of DKD in patients (OR=1.80, 95% CI 1.16 to 2.80, P=0.008). CONCLUSIONS The genetic polymorphisms rs11879029 and rs11879010 of SIRT2 gene are potential contributors to the susceptibility of DKD in patients with T2DM, and allele A significantly increases the risk of DKD compared with allele G. The AA genotype might be a genetic risk factor for DKD.
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Affiliation(s)
- Su Wu
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013.
- Department of Nephrology, Fourth Hospital of Changsha, Changsha 410017, China.
| | - Bin Yi
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013.
| | - Yali Dai
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Xiangyu Liao
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Juan Peng
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Aimei Li
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013.
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Kiconco R, Kalyesubula R, Kiwanuka GN. Distribution of the ACE Gene Polymorphisms in Type 2 Diabetes Mellitus Patients, Their Associations with Nephropathy Biomarkers and Metabolic Indicators at a Tertiary Hospital in Uganda. Diabetes Metab Syndr Obes 2024; 17:2211-2220. [PMID: 38854447 PMCID: PMC11162639 DOI: 10.2147/dmso.s462740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/23/2024] [Indexed: 06/11/2024] Open
Abstract
Purpose We aimed at determining the distribution of the ACE insertion/deletion gene polymorphisms among type 2 diabetic patients and their association with the nephropathy biomarkers and the metabolic indicators. Patients and Methods Data were collected from 237 adult type 2 diabetes mellitus patients receiving healthcare at the diabetic clinic of Mbarara Regional Referral Hospital. Peripheral blood genomic DNA was amplified using a conventional PCR technique and analyzed for the ACE homozygous forms of the insertion (II), deletion (DD) and heterozygous insertion deletion (ID) genotypes as well as their respective allele counts. Biomarkers of nephropathy were analyzed on a Beckman coulter AU480 chemistry analyzer using system compatible reagents. Results Majority of the participants were older persons (Median = 57, IQR = 49-64) and female 171 (72.2%). Most of them had the Deletion allele 198 (83.5%) and DD genotype 116 (48.9%). At multivariate logistic regression, the nephropathy biomarkers that is microalbuminuria, serum creatinine, urea, eGFR and electrolytes had no association with the ACE I/D alleles or genotypes (p > 0.05). On the other hand, selected metabolic indicators had a positive relationship. The insertion allele was associated with increasing glycated hemoglobin (OR = 1.082, p = 0.019) and decreasing serum glucose levels (OR = 0.891, p = 0.001). Deletion allele was associated with decreasing glycated hemoglobin (OR = 0.924, p = 0.047) and increasing serum glucose levels (OR = 1.208, p = 0.001). ACE II genotype was associated with decreasing serum glucose levels (OR = 0.873, p = 0.029). ACE DD genotype was associated with decreasing glycated hemoglobin (OR = 0.917, p = 0.010) and increasing serum glucose levels (OR = 1.132, p = 0.001). ACE ID genotype was associated with increasing glycated hemoglobin (OR = 1.077, p = 0.022), triglyceride levels (OR = 1.316, p = 0.031) and decreasing serum glucose levels (OR = 0.933, p = 0.038). Conclusion The presence or absence of the ACE I/D alleles and genotypes affects the ultimate increase or decrease in the serum glucose, glycated hemoglobin and triglyceride levels. Although there was no significant association between the biomarkers of nephropathy and the ACE I/D alleles or genotypes, the above implicated metabolic indicators should be included in healthcare guidelines used when attending to type 2 diabetic patients.
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Affiliation(s)
- Ritah Kiconco
- Department of Medical Laboratory Science, Mbarara University of Science and Technology, Mbarara, Uganda
- Department of Biochemistry, Soroti University, Soroti, Uganda
| | - Robert Kalyesubula
- Departments of Internal Medicine and Physiology, Makerere University, Kampala, Uganda
| | - Gertrude N Kiwanuka
- Department of Biochemistry, Mbarara University of Science and Technology, Mbarara, Uganda
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Qiu J, Yard BA, Krämer BK, Bilo HJG, Kannt A, van Goor H, van Dijk PR. Serum carnosinase 1, an early indicator for incident microalbuminuria in type 1 diabetes. J Diabetes Metab Disord 2024; 23:1271-1277. [PMID: 38932803 PMCID: PMC11196470 DOI: 10.1007/s40200-024-01422-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/08/2024] [Indexed: 06/28/2024]
Abstract
Aims Carnosinase (CN1) polymorphisms have been linked to diabetic kidney disease (DKD), as CN1 degrades dipeptides which scavenge oxidative metabolites and prevent the formation of advanced glycation end-products. In this work, we studied the association between serum CN1, the systemic redox status and long-term renal outcome in type 1 diabetes. Methods Serum CN1 was measured in a prospective type 1 diabetes cohort (n = 218) with a 16-year follow-up. A total of 218 patients treated at the Diabetes Outpatient Clinic of the Weezenlanden Hospital (nowadays Isala Hospital, Zwolle, The Netherlands) were included in this analysis. We assessed whether serum CN1 was associated with renal function and development of DKD as well as other diabetic complications. Results At baseline, age, systemic redox status and N-terminal pro brain-natriuretic peptide (NT-proBNP) were associated with serum CN1 concentration (p < 0.05). During follow-up, CN1 concentration in the middle tertile was associated with less incident microalbuminuria (odds ratio = 0.194, 95% C.I.: 0.049-0.772, p = 0.02) after adjustment for age, systemic redox status, NT-proBNP and sex. Discussion Serum CN1 could predict incident microalbuminuria and may be used as a novel parameter to identify patients at risk for DKD.
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Affiliation(s)
- Jiedong Qiu
- 5Th Medical Department, University Hospital Mannheim, Heidelberg University, E68167 Mannheim, Germany
- Department of Pathology and Medical Biology, University Medical Centre Groningen and University of Groningen, NL-9713 GZ Groningen, the Netherlands
| | - Benito A. Yard
- 5Th Medical Department, University Hospital Mannheim, Heidelberg University, E68167 Mannheim, Germany
| | - Bernhard K. Krämer
- 5Th Medical Department, University Hospital Mannheim, Heidelberg University, E68167 Mannheim, Germany
| | - Henk J. G. Bilo
- Department of Internal Medicine, University Medical Centre Groningen and University of Groningen, NL-9713 GZ Groningen, the Netherlands
- Isala Diabetes Centre, NL-8025 AB Zwolle, the Netherlands
| | - Aimo Kannt
- 5Th Medical Department, University Hospital Mannheim, Heidelberg University, E68167 Mannheim, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology, E60596 Frankfurt, Germany
| | - Harry van Goor
- Department of Pathology and Medical Biology, University Medical Centre Groningen and University of Groningen, NL-9713 GZ Groningen, the Netherlands
| | - Peter R. van Dijk
- Department of Internal Medicine, University Medical Centre Groningen and University of Groningen, NL-9713 GZ Groningen, the Netherlands
- Isala Diabetes Centre, NL-8025 AB Zwolle, the Netherlands
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Pan Y, Zhou M, Liu Z, Hao C, Zhai J, Liu R, Shi Z, Sun J, Wang X. Synthesis and activity of arylcoumarin derivatives with therapeutic effects on diabetic nephropathy. Arch Pharm (Weinheim) 2024; 357:e2300524. [PMID: 38036297 DOI: 10.1002/ardp.202300524] [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: 09/20/2023] [Revised: 11/09/2023] [Accepted: 11/09/2023] [Indexed: 12/02/2023]
Abstract
In the literature, daidzein has been reported to exhibit cardiovascular protective effects and hypoglycemic activity in mice. We sought to design and synthesize a novel compound, SJ-6, an analog of daidzein, with improved hypoglycemic properties. Although SJ-6 demonstrated favorable hypoglycemic effects, its pharmacokinetic limitations prompted us to design and synthesize prodrugs of SJ-6. We conducted a comprehensive evaluation of the prodrugs, including in vitro and in vivo studies, such as cytotoxicity, absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulation analysis, in vitro blood-brain barrier (BBB) permeability evaluation, compound effect on insulin resistance, oral glucose tolerance test (OGTT), in vivo plasma concentration testing, acute toxicity test in rats, and long-term gavage administration experiment. Furthermore, we examined the antidiabetic nephropathy activity of our lead compound, compound 10, which demonstrated superior efficacy compared with the positive control drug, metformin hydrochloride. Our findings suggest that compound 10 represents a promising lead compound for the prevention and treatment of diabetic nephropathy.
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Affiliation(s)
- Yinbo Pan
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
- School of Chemistry and Chemical Engineering, School of Biological Science and Technology, University of Jinan, Jinan, China
| | - Min Zhou
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Zhenzhen Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Canhua Hao
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Jingfang Zhai
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Ren Liu
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Zezhou Shi
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Jie Sun
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
| | - Xiaojing Wang
- School of Parmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Ji'nan, Shandong, 250117, China
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Azarboo A, Hosseinkhani S, Ghaseminejad-Raeini A, Aazami H, Mohammadi SM, Zeidi S, Razi F, Bandarian F. Association between ELMO1 gene polymorphisms and diabetic kidney disease: A systematic review and meta-analysis. PLoS One 2024; 19:e0295607. [PMID: 38277369 PMCID: PMC10817128 DOI: 10.1371/journal.pone.0295607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/25/2023] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Previous research has suggested that the ELMO1 gene may play a role in the development of diabetic kidney disease. Diabetic kidney disease (DKD) is a serious complication of diabetes and the leading cause of chronic kidney disease and end-stage renal disease (ESRD). OBJECTIVE AND RATIONALE This study aim was to systematically review and explore the association between ELMO1 gene polymorphisms and diabetic kidney disease. A comprehensive systematic review provides a clear conclusion and high-level evidence for the association between ELMO1 gene and DKD for future application in personalized medicine. METHODS A comprehensive search of electronic databases, per PRISMA instructions, was conducted in Scopus, EMBASE, Web of Science, and PubMed databases from 1980 to January 2023. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using appropriate models. Subgroup and sensitivity analyses were performed to explore potential sources of heterogeneity and assess the robustness of the findings. RESULTS A total of 5794 diabetes patients with DKD, 4886 diabetes patients without DKD, and 2023 healthy controls were included in the 17 studies that made up this systematic review. In the investigation of DM (Diabetes Mellitus) with DKD vs. DM without DKD, the susceptibility for DKD for the EMLO1 rs741301 polymorphism indicated a significant difference under the dominant, homozygote, and recessive genetic models. The susceptibility for DKD for the EMLO1 rs1345365, rs10255208, and rs7782979 polymorphisms demonstrated a significant difference under the allele genetic models in the analysis of DM with DKD vs. DM without DKD groups. There was a considerable increase in DKD risk in the Middle East when the population was stratified by the region. CONCLUSION The findings of the meta-analysis show that there are a significant connection between the EMLO1 rs741301 polymorphism and DKD susceptibility in overall analyses; as well as rs1345365, rs10255208, and rs7782979 polymorphisms; especially in the Middle East region.
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Affiliation(s)
- Alireza Azarboo
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Hosseinkhani
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Ghaseminejad-Raeini
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Aazami
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed Mohammad Mohammadi
- Evidence Based Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Zeidi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Razi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bandarian
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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8
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Li M, Armelloni S, Mattinzoli D, Ikehata M, Chatziantoniou C, Alfieri C, Molinari P, Chadjichristos CE, Malvica S, Castellano G. Crosstalk mechanisms between glomerular endothelial cells and podocytes in renal diseases and kidney transplantation. Kidney Res Clin Pract 2024; 43:47-62. [PMID: 38062623 PMCID: PMC10846991 DOI: 10.23876/j.krcp.23.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 07/20/2023] [Accepted: 08/10/2023] [Indexed: 02/06/2024] Open
Abstract
The glomerular filtration barrier (GFB), composed of endothelial cells, glomerular basement membrane, and podocytes, is a unique structure for filtering blood while detaining plasma proteins according to size and charge selectivity. Structurally, the fenestrated endothelial cells, which align the capillary loops, are in close proximity to mesangial cells. Podocytes are connected by specialized intercellular junctions known as slit diaphragms and are separated from the endothelial compartment by the glomerular basement membrane. Podocyte-endothelial cell communication or crosstalk is required for the development and maintenance of an efficient filtration process in physiological conditions. In pathological situations, communication also has an essential role in promoting or delaying disease progression. Podocytes and endothelial cells can secrete signaling molecules, which act as crosstalk effectors and, through binding to their target receptors, can trigger bidirectional paracrine or autocrine signal transduction. Moreover, the emerging evidence of extracellular vesicles derived from various cell types engaging in cell communication has also been reported. In this review, we summarize the principal pathways involved in the development and maintenance of the GFB and the progression of kidney disease, particularly in kidney transplantation.
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Affiliation(s)
- Min Li
- Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Silvia Armelloni
- Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Deborah Mattinzoli
- Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Masami Ikehata
- Renal Research Laboratory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Christos Chatziantoniou
- Unité Mixte de Recherche Scientifique 1155, Institut National de la Santé et de la Recherche Médicale, Hôpital Tenon, Paris, France
- Faculty of Medicine, Sorbonne University, Paris, France
| | - Carlo Alfieri
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Paolo Molinari
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Christos E. Chadjichristos
- Unité Mixte de Recherche Scientifique 1155, Institut National de la Santé et de la Recherche Médicale, Hôpital Tenon, Paris, France
- Faculty of Medicine, Sorbonne University, Paris, France
| | - Silvia Malvica
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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9
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Liu S, Zhang F, Liang Y, Wu G, Liu R, Li X, Saw PE, Yang Z. Nanoparticle (NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2451-2465. [PMID: 37668862 DOI: 10.1007/s11427-022-2329-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 03/14/2023] [Indexed: 09/06/2023]
Abstract
Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.
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Affiliation(s)
- Shaomin Liu
- Department of Biochemistry, Molecular Cancer Research Center, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Fengqian Zhang
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, 528200, China
| | - Yixia Liang
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, 528200, China
| | - Guo Wu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang, 421001, China
| | - Rong Liu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang, 421001, China
| | - Xiuling Li
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, 528200, China
| | - Phei Er Saw
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan, 528200, China.
| | - Zhonghan Yang
- Department of Biochemistry, Molecular Cancer Research Center, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
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10
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Lu Y, Wang W, Liu J, Xie M, Liu Q, Li S. Vascular complications of diabetes: A narrative review. Medicine (Baltimore) 2023; 102:e35285. [PMID: 37800828 PMCID: PMC10553000 DOI: 10.1097/md.0000000000035285] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/28/2023] [Indexed: 10/07/2023] Open
Abstract
Diabetes mellitus is a complex chronic metabolic disease characterized by hyperglycemia and various complications. According to the different pathophysiological mechanisms, these complications can be classified as microvascular or macrovascular complications, which have long-term negative effects on vital organs such as the eyes, kidneys, heart, and brain, and lead to increased patient mortality. Diabetes mellitus is a major global health issue, and its incidence and prevalence have increased significantly in recent years. Moreover, the incidence is expected to continue to rise as more people adopt a Western lifestyle and diet. Thus, it is essential to understand the epidemiology, pathogenesis, risk factors, and treatment of vascular complications to aid patients in managing the disease effectively. This paper provides a comprehensive review of the literature to clarify the above content. Furthermore, this paper also delves into the correlation between novel risk factors, such as long noncoding RNAs, gut microbiota, and nonalcoholic fatty liver disease, with diabetic vascular complications.
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Affiliation(s)
- Yongxia Lu
- Department of Endocrinology and Metabolism, Chengdu Seventh People’s Hospital, Chengdu, China
| | - Wei Wang
- Department of Endocrinology and Metabolism, Chengdu Seventh People’s Hospital, Chengdu, China
| | - Jingyu Liu
- Department of Endocrinology and Metabolism, Chengdu Seventh People’s Hospital, Chengdu, China
| | - Min Xie
- Department of Cardiovascular Medicine, Chengdu Seventh People’s Hospital, Chengdu, China
| | - Qiang Liu
- Department of Endocrinology and Metabolism, Chengdu Seventh People’s Hospital, Chengdu, China
| | - Sufang Li
- Department of Endocrinology and Metabolism, Chengdu Seventh People’s Hospital, Chengdu, China
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11
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Sandholm N, Dahlström EH, Groop PH. Genetic and epigenetic background of diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1163001. [PMID: 37324271 PMCID: PMC10262849 DOI: 10.3389/fendo.2023.1163001] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/10/2023] [Indexed: 06/17/2023] Open
Abstract
Diabetic kidney disease (DKD) is a severe diabetic complication that affects up to half of the individuals with diabetes. Elevated blood glucose levels are a key underlying cause of DKD, but DKD is a complex multifactorial disease, which takes years to develop. Family studies have shown that inherited factors also contribute to the risk of the disease. During the last decade, genome-wide association studies (GWASs) have emerged as a powerful tool to identify genetic risk factors for DKD. In recent years, the GWASs have acquired larger number of participants, leading to increased statistical power to detect more genetic risk factors. In addition, whole-exome and whole-genome sequencing studies are emerging, aiming to identify rare genetic risk factors for DKD, as well as epigenome-wide association studies, investigating DNA methylation in relation to DKD. This article aims to review the identified genetic and epigenetic risk factors for DKD.
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Affiliation(s)
- Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Emma H. Dahlström
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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12
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The genetic side of diabetic kidney disease: a review. Int Urol Nephrol 2023; 55:335-343. [PMID: 35974289 DOI: 10.1007/s11255-022-03319-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/24/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is one of the most common complications of diabetes, with approximately 30-40% of patients with type 1 diabetes mellitus and 20% of patients with type 2 diabetes mellitus eventually developing DKD. If DKD is not controlled in the early clinical stage and proteinuria develops, the disease will progress to end-stage renal disease. The pathogenesis of DKD remains largely unknown and is multifactorial, likely due to interactions between genetic and environmental factors. Familial clustering also supports a critical role of hereditary factors in DKD. The development of gene detection technology has promoted the exploration of DKD susceptibility genes in different cohorts of patients with diabetes. Identifying susceptibility genes can provide insights into the pathogenesis of DKD, as well as a basis for its clinical diagnosis and therapy. RESULTS Numerous candidate gene loci have been found to be associated with DKD, many of which play critical regulatory roles in the pathogenesis of this disease, including genes involved in glycol-metabolism, lipid metabolism, the renin-angiotensin-aldosterone system, inflammation and oxidative stress. In this review, we summarize the functions of several susceptibility genes involved in the development of DKD. CONCLUSION Based on our findings, we recommend that studying susceptibility gene polymorphisms can lead to a better understanding of the pathogenesis of DKD and could help prevent this disease or improve its outcomes.
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13
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Zhang S, Cui D, Tang M, Yang G, Yard B, Hu H, Wu Y, Zhang Q. Serum and urinary carnosinase-1 correlate with kidney function and inflammation. Amino Acids 2023; 55:89-100. [PMID: 36319874 PMCID: PMC9877089 DOI: 10.1007/s00726-022-03206-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 09/22/2022] [Indexed: 11/05/2022]
Abstract
The carnosinase dipeptidase 1 (CNDP1) gene has been reported as a susceptibility locus for the development of diabetic kidney disease (DKD). While the (CTG)5 allele affords protection in the Caucasian population, we have previously shown that this allele is less frequently present in the Chinese population and therefore a protective role for the (CTG)5 allele is difficult to demonstrate. In the present study, we sought to assess if carnosinase-1 (CN-1) concentrations in serum and/or urine are associated with progression of DKD and to what extent CN-1 influences diabetes-associated inflammation. From a total of 622 individuals that enrolled in our study, 247 patients had type 2 diabetes without DKD, 165 patients had DKD and 210 subjects served as healthy controls. Uni- and multivariate regression analyses were performed to identify potential factors predicting urinary albumin creatinine ratio (UACR), estimated glomerular filtration rate (eGFR) and CN-1 concentration in serum and urine. The results indicated that serum CN-1 indeed correlated with eGFR (p = 0.001). In addition, urinary CN-1 associated with eGFR and tubular injury indicator: urinary cystatin C (Cys-C) and urinary retinol-binding protein (RBP). Interestingly, serum CN-1 also positively correlated with inflammatory indicators: neutrophils and lymphocytes. With regard to this, a STZ injected C57BL/6 mice model with surgically made skin wound was established for the generation of skin inflammation. This animal model further proved that the expression of CN-1 in liver and kidney increased remarkably in diabetic mice with skin wound as compared to those without. In conclusion, serum and urinary CN-1 significantly related to the surrogates of impaired renal function in diabetic patients; besides, CN-1 expression might also be associated with the process of inflammation.
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Affiliation(s)
- Shiqi Zhang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Di Cui
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Mingna Tang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Guang Yang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Benito Yard
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Huaqing Hu
- Health Management Center, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Yonggui Wu
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
| | - Qiu Zhang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 China
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14
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Rouland A, Masson D, Lagrost L, Vergès B, Gautier T, Bouillet B. Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a systematic review. Cardiovasc Diabetol 2022; 21:272. [PMID: 36471375 PMCID: PMC9724408 DOI: 10.1186/s12933-022-01703-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.
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Affiliation(s)
- Alexia Rouland
- grid.31151.37Endocrinology and Diabetology Unit, University Hospital, Dijon, France ,grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France
| | - David Masson
- grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France ,LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Laurent Lagrost
- grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France ,LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Bruno Vergès
- grid.31151.37Endocrinology and Diabetology Unit, University Hospital, Dijon, France ,grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France
| | - Thomas Gautier
- grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France ,LipSTIC LabEx, UFR Sciences de Santé, Dijon, France
| | - Benjamin Bouillet
- grid.31151.37Endocrinology and Diabetology Unit, University Hospital, Dijon, France ,grid.493090.70000 0004 4910 6615INSERM/University of Bourgogne Franche-Comté, LNC UMR1231, Dijon, France ,grid.31151.37Service Endocrinologie, Diabétologie et Maladies Métaboliques, Hôpital François Mitterrand, CHU Dijon, BP 77908, 21079 Dijon, France
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15
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Yu Y, Zhang YH, Liu L, Yu LL, Li JP, Rao JA, Hu F, Zhu LJ, Bao HH, Cheng XS. Bioinformatics analysis of candidate genes and potential therapeutic drugs targeting adipose tissue in obesity. Adipocyte 2022; 11:1-10. [PMID: 34964707 PMCID: PMC8726706 DOI: 10.1080/21623945.2021.2013406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Obesity is a complex medical condition that affects multiple organs in the body. However, the underlying mechanisms of obesity, as well as its treatment, are largely unexplored. The focus of this research was to use bioinformatics to discover possible treatment targets for obesity. To begin, the GSE133099 database was used to identify 364 differentially expressed genes (DEGs). Then, DEGs were subjected to tissue-specific analyses and enrichment analyses, followed by the creation of a protein-protein interaction (PPI) network and generation of a drug-gene interaction database to screen key genes and potential future drugs targeting obesity. Findings have illustrated that the tissue-specific expression of neurologic markers varied significantly (34.7%, 52/150). Among these genes, Lep, ApoE, Fyn, and FN1 were the key genes observed in the adipocyte samples from obese patients relative to the controls. Furthermore, nine potential therapeutic drugs (dasatinib, ocriplasmin, risperidone, gemfibrozil, ritonavir, fluvastatin, pravastatin, warfarin, atorvastatin) that target the key genes were also screened and selected. To conclude the key genes discovered (Lep, ApoE, Fyn, and FN1), as well as 9 candidate drugs, could be used as therapeutic targets in treating obesity.
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Affiliation(s)
- Yun Yu
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yu-Han Zhang
- Reproductive Medical Center, Maternal and Child Health Affiliated Hospital of Nanchang University, Nanchang, China
| | - Liang Liu
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ling-Ling Yu
- Department of Rehabilitation, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun-Pei Li
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing-an Rao
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Feng Hu
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ling-Juan Zhu
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hui-Hui Bao
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao-Shu Cheng
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China
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16
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Hacıoğlu Y, Pişkinpaşa ME, Kılıçkaya P, Niyazoğlu M, Hacıoğlu B, Hatipoğlu E. Increased Serum Growth Differentiation Factor 15 Levels may be Associated with Diastolic Dysfunction in Acromegaly. ISTANBUL MEDICAL JOURNAL 2022. [DOI: 10.4274/imj.galenos.2022.44788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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17
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Dong R, Xu Y. Glomerular cell cross talk in diabetic kidney diseases. J Diabetes 2022; 14:514-523. [PMID: 35999686 PMCID: PMC9426281 DOI: 10.1111/1753-0407.13304] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/19/2022] [Accepted: 07/29/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes mellitus. It is the leading inducement of end-stage renal disease (ESRD), and its global incidence has been increasing at an alarming rate. The strict control of blood pressure and blood glucose can delay the progression of DKD, but intensive treatment is challenging to maintain. Studies to date have failed to find a complete cure. The glomerulus's alterations and injuries play a pivotal role in the initiation and development of DKD. A wealth of data indicates that the interdependent relationship between resident cells in the glomerulus will provide clues to the mechanism of DKD and new ways for therapeutic intervention. This review summarizes the significant findings of glomerular cell cross talk in DKD, focusing on cellular signaling pathways, regulators, and potential novel avenues for treating progressive DKD.
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Affiliation(s)
- Ruixue Dong
- Faculty of Pharmacy, Macau University of Science and Technology, Taipa, Macau, People's Republic of China
| | - Youhua Xu
- Faculty of Pharmacy, Macau University of Science and Technology, Taipa, Macau, People's Republic of China
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, People's Republic of China
- Department of Endocrinology, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, People's Republic of China
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18
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Asociación del polimorfismo rs5186 del gen AGTR1 con disminución de la TFGe en pacientes con diabetes tipo 2 de la Ciudad de México. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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19
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Ma RCW, Xie F, Lim CKP, Lau ESH, Luk AOY, Ozaki R, Cheung GPY, Lee HM, Ng ACW, Li HW, Wong CKM, Wong SYS, So WY, Chan JCN. A randomized clinical trial of genetic testing and personalized risk counselling in patients with type 2 diabetes receiving integrated care -The genetic testing and patient empowerment (GEM) trial. Diabetes Res Clin Pract 2022; 189:109969. [PMID: 35728675 DOI: 10.1016/j.diabres.2022.109969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/05/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022]
Abstract
AIMS We evaluated the effect of personalized risk counseling incorporating clinical and genetic risk factors on patient empowerment and risk factor control in diabetes. METHODS Patients with type 2 diabetes (T2D) with suboptimal glycaemic control (HbA1c ≥ 7.5%) were randomized to a genetic counselling (GC) or control group. All patients underwent genetic testing for alleles at three loci associated with diabetic complications. The GC group received additional explanation of the joint associations of genetic and modifiable risk factors on risk of complications. All patients were reassessed at 12 months including validated questionnaires for patient reported outcomes. The primary outcome was proportion of patients reaching ≥ 3 of 5 predefined treatment targets (HbA1c < 7%, BP < 130/80 mmHg, LDL-C < 2.6 mmol/L, Triglyceride < 2.0 mmol/L, use of renin-angiotensin system inhibitors). Secondary outcomes included new-onset chronic kidney disease or microalbuminuria and patient reported outcome measures. RESULTS A total of 435 patients were randomized and 420 patients were included in the modified intention-to-treat analysis. At 12 months, the proportion of patients who attained ≥ 3 targets increased from 41.6% to 52.3% in the GC group (p = 0.007) versus 49.5% to 62.6% in the control group (p = 0.003), without between-group difference. Both groups had similar reduction in HbA1c, LDL-C and increased use of medications. In per protocol analysis, the GC group had higher diabetes empowerment, with reduced diabetes distress. In the GC group, the greatest improvement in positive attitude and self-care activities was observed in the intermediate to high genetic risk score (GRS) groups. CONCLUSIONS In patients with T2D receiving integrated care, additional counselling on genetic risk of complications did not further improve risk factor control, although the improvement in self-efficacy warrants long-term evaluation.
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Affiliation(s)
- Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, China.
| | - Fangying Xie
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
| | - Cadmon King Poo Lim
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, China.
| | - Eric Siu Him Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
| | - Andrea On Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, China.
| | - Risa Ozaki
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Grace Pui Yiu Cheung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
| | - Heung Man Lee
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
| | - Alex Chi Wai Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
| | - Heung Wing Li
- The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China.
| | - Carmen Ka Man Wong
- The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China.
| | - Samuel Yeung Shan Wong
- The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China.
| | - Wing Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Juliana Chung Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, China.
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20
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Yang J, Liu Z. Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy. Front Endocrinol (Lausanne) 2022; 13:816400. [PMID: 35692405 PMCID: PMC9174994 DOI: 10.3389/fendo.2022.816400] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/28/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are microvascular complications of diabetes. Microvascular endothelial cells are thought to be the major targets of hyperglycemic injury. In diabetic microvasculature, the intracellular hyperglycemia causes damages to the vascular endothelium, via multiple pathophysiological process consist of inflammation, endothelial cell crosstalk with podocytes/pericytes and exosomes. In addition, DN and DR diseases development are involved in several critical regulators including the cell adhesion molecules (CAMs), the vascular endothelial growth factor (VEGF) family and the Notch signal. The present review attempts to gain a deeper understanding of the pathogenesis complexities underlying the endothelial dysfunction in diabetes diabetic and retinopathy, contributing to the development of new mechanistic therapeutic strategies against diabetes-induced microvascular endothelial dysfunction.
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Affiliation(s)
- Jing Yang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center For Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhangsuo Liu
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center For Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Babayeva M, Azzi B, Loewy ZG. Pharmacogenomics Informs Cardiovascular Pharmacotherapy. Methods Mol Biol 2022; 2547:201-240. [PMID: 36068466 DOI: 10.1007/978-1-0716-2573-6_9] [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] [Indexed: 06/15/2023]
Abstract
Precision medicine exemplifies the emergence of personalized treatment options which may benefit specific patient populations based upon their genetic makeup. Application of pharmacogenomics requires an understanding of how genetic variations impact pharmacokinetic and pharmacodynamic properties. This particular approach in pharmacotherapy is helpful because it can assist in and improve clinical decisions. Application of pharmacogenomics to cardiovascular pharmacotherapy provides for the ability of the medical provider to gain critical knowledge on a patient's response to various treatment options and risk of side effects.
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Affiliation(s)
| | | | - Zvi G Loewy
- Touro College of Pharmacy, New York, NY, USA.
- School of Medicine, New York Medical College, Valhalla, NY, USA.
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22
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Liu ZL, Wang XQ, Liu MF, Ye BJ. Meta-analysis of association between TPH2 single nucleotide poiymorphism and depression. Neurosci Biobehav Rev 2021; 134:104517. [PMID: 34979191 DOI: 10.1016/j.neubiorev.2021.104517] [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: 10/11/2020] [Revised: 11/14/2021] [Accepted: 12/29/2021] [Indexed: 10/19/2022]
Abstract
Tryptophan hydroxylase 2 (TPH2) plays a crucial role in the human brain. Although the association between the TPH2 gene and depression has been suggested in previous meta-analyses, studies based on Chinese subjects are often neglected. Therefore, we included some previous studies based on Chinese subjects to explore the relationship between TPH2 polymorphisms and depression via conducting an extensive meta-analysis. We reviewed 40 research papers that included data on TPH2 gene single nucleotide polymorphisms (SNPs) from 5766 patients with depression and 5988 healthy subjects. The analysis showed an association between polymorphisms in the TPH2 gene and depression, and some results were significant in 24 studies that included Chinese Han study participants. The results of our meta-analysis showed that rs4570625, rs17110747, rs120074175, rs4290270, rs120074175, and rs4290270 may be significantly associated with depression, and that rs11178997 (A/A genotype) may be a significant risk factor for depression in the Chinese subjects. Based on the results of this study, biological experiments should be performed in the future to explore how different SNPs affect depression.
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Affiliation(s)
- Zhang-Lin Liu
- School of Psychology, Center of Mental Health Education and Research, Key Laboratory of Psychology and Cognition Science of Jiangxi, Jiangxi Normal University, China.
| | - Xin-Qiang Wang
- School of Psychology, Center of Mental Health Education and Research, Key Laboratory of Psychology and Cognition Science of Jiangxi, Jiangxi Normal University, China.
| | - Ming-Fan Liu
- School of Psychology, Center of Mental Health Education and Research, Key Laboratory of Psychology and Cognition Science of Jiangxi, Jiangxi Normal University, China.
| | - Bao-Juan Ye
- School of Psychology, Center of Mental Health Education and Research, Key Laboratory of Psychology and Cognition Science of Jiangxi, Jiangxi Normal University, China.
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23
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OMICS in Chronic Kidney Disease: Focus on Prognosis and Prediction. Int J Mol Sci 2021; 23:ijms23010336. [PMID: 35008760 PMCID: PMC8745343 DOI: 10.3390/ijms23010336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 12/26/2021] [Accepted: 12/27/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic kidney disease (CKD) patients are characterized by a high residual risk for cardiovascular (CV) events and CKD progression. This has prompted the implementation of new prognostic and predictive biomarkers with the aim of mitigating this risk. The ‘omics’ techniques, namely genomics, proteomics, metabolomics, and transcriptomics, are excellent candidates to provide a better understanding of pathophysiologic mechanisms of disease in CKD, to improve risk stratification of patients with respect to future cardiovascular events, and to identify CKD patients who are likely to respond to a treatment. Following such a strategy, a reliable risk of future events for a particular patient may be calculated and consequently the patient would also benefit from the best available treatment based on their risk profile. Moreover, a further step forward can be represented by the aggregation of multiple omics information by combining different techniques and/or different biological samples. This has already been shown to yield additional information by revealing with more accuracy the exact individual pathway of disease.
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24
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Saracyn M, Kisiel B, Franaszczyk M, Brodowska-Kania D, Żmudzki W, Małecki R, Niemczyk L, Dyrla P, Kamiński G, Płoski R, Niemczyk S. Diabetic kidney disease: Are the reported associations with single-nucleotide polymorphisms disease-specific? World J Diabetes 2021; 12:1765-1777. [PMID: 34754377 PMCID: PMC8554375 DOI: 10.4239/wjd.v12.i10.1765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/26/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The genetic backgrounds of diabetic kidney disease (DKD) and end-stage kidney disease (ESKD) have not been fully elucidated. AIM To examine the individual and cumulative effects of single-nucleotide polymorphisms (SNPs) previously associated with DKD on the risk for ESKD of diabetic etiology and to determine if any associations observed were specific for DKD. METHODS Fourteen SNPs were genotyped in hemodialyzed 136 patients with diabetic ESKD (DKD group) and 121 patients with non-diabetic ESKD (NDKD group). Patients were also re-classified on the basis of the primary cause of chronic kidney disease (CKD). The distribution of alleles was compared between diabetic and non-diabetic groups as well as between different sub-phenotypes. The weighted multilocus genetic risk score (GRS) was calculated to estimate the cumulative risk conferred by all SNPs. The GRS distribution was then compared between the DKD and NDKD groups as well as in the groups according to the primary cause of CKD. RESULTS One SNP (rs841853; SLC2A1) showed a nominal association with DKD (P = 0.048; P > 0.05 after Bonferroni correction). The GRS was higher in the DKD group (0.615 ± 0.260) than in the NDKD group (0.590 ± 0.253), but the difference was not significant (P = 0.46). The analysis of associations between GRS and individual factors did not show any significant correlation. However, the GRS was significantly higher in patients with glomerular disease than in those with tubulointerstitial disease (P = 0.014) and in those with a combined group (tubulointerstitial, vascular, and cystic and congenital disease) (P = 0.018). CONCLUSION Our results suggest that selected SNPs that were previously associated with DKD may not be specific for DKD and may confer risk for CKD of different etiology, particularly those affecting renal glomeruli.
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Affiliation(s)
- Marek Saracyn
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw 04-141, Poland
- Department of Endocrinology and Isotope Therapy, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Bartłomiej Kisiel
- Clinical Research Support Center, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Maria Franaszczyk
- Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw 04-628, Poland
| | - Dorota Brodowska-Kania
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw 04-141, Poland
- Department of Endocrinology and Isotope Therapy, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Wawrzyniec Żmudzki
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Robert Małecki
- Department of Nephrology, Międzyleski Specialist Hospital in Warsaw, Warsaw 04-749, Poland
| | - Longin Niemczyk
- Department of Nephrology, Dialysis and Internal Diseases, Warsaw Medical University, Warsaw 02-097, Poland
| | - Przemysław Dyrla
- Department of Gastroenterology, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Grzegorz Kamiński
- Department of Endocrinology and Isotope Therapy, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw 02-106, Poland
| | - Stanisław Niemczyk
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw 04-141, Poland
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25
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Tziastoudi M, Tsezou A, Stefanidis I. Cadherin and Wnt signaling pathways as key regulators in diabetic nephropathy. PLoS One 2021; 16:e0255728. [PMID: 34411124 PMCID: PMC8375992 DOI: 10.1371/journal.pone.0255728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
AIM A recent meta-analysis of genome-wide linkage studies (GWLS) has identified multiple genetic regions suggestive of linkage with DN harboring hundreds of genes. Moving this number of genetic loci forward into biological insight is truly the next step. Here, we approach this challenge with a gene ontology (GO) analysis in order to yield biological and functional role to the genes, an over-representation test to find which GO terms are enriched in the gene list, pathway analysis, as well as protein network analysis. METHOD GO analysis was performed using protein analysis through evolutionary relationships (PANTHER) version 14.0 software and P-values less than 0.05 were considered statistically significant. GO analysis was followed by over-representation test for the identification of enriched terms. Statistical significance was calculated by Fisher's exact test and adjusted using the false discovery rate (FDR) for correction of multiple tests. Cytoscape with the relevant plugins was used for the construction of the protein network and clustering analysis. RESULTS The GO analysis assign multiple GO terms to the genes regarding the molecular function, the biological process and the cellular component, protein class and pathway analysis. The findings of the over-representation test highlight the contribution of cell adhesion regarding the biological process, integral components of plasma membrane regarding the cellular component, chemokines and cytokines with regard to protein class, while the pathway analysis emphasizes the contribution of Wnt and cadherin signaling pathways. CONCLUSIONS Our results suggest that a core feature of the pathogenesis of DN may be a disturbance in Wnt and cadherin signaling pathways, whereas the contribution of chemokines and cytokines need to be studied in additional studies.
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Affiliation(s)
- Maria Tziastoudi
- Department of Nephrology, School of Medicine, University of Thessaly, Larissa, Greece
| | - Aspasia Tsezou
- Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
- Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Ioannis Stefanidis
- Department of Nephrology, School of Medicine, University of Thessaly, Larissa, Greece
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26
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A Case of Lupus Nephritis Aggravated by Diabetic Nephropathy with a Rapid Decline in Kidney Function. ACTA MEDICA BULGARICA 2021. [DOI: 10.2478/amb-2021-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Lupus nephropathy is a glomerular lesion and one of the most severe organ localizations of systemic lupus erythematosus (SLE). Diabetic nephropathy, on the other hand, is a major cause for chronic kidney disease (CKD) as well as for end stage kidney disease (ESKD). We present the case of a 51-year-old woman with nephrotic syndrome diagnosed 4 months previously. Since the diagnosis was made, a rapid decline in renal function was observed – serum creatinine rose from 159 to 200 and to 462 μmol/l. Arterial hypertension was present for 2 years with BP values up to 200/90 mm Hg, as well as newly diagnosed diabetes mellitus which was insulin-treated due to the low renal function. The test for anti-dsDNA-63.3 was positive and ANA titers were 1: 320. The renal biopsy revealed a combination of lupus nephropathy and a nodular variant of diabetic nephropathy. Treatment with methylprednisolone, cyclophosphamide and heparin was initiated. This was followed by improvement in serum creatinine and proteinuria, by reduction of edema, decreased titers of anti-dsDNA and by improvement of the general well-being. A few months later, in the course of another intermittent infection, the patient’s condition deteriorated sharply, necessitating hemodialysis. Nephropathy secondary to lupus erythematosus is rarely seen in combination with diabetic nephropathy, but once they co-occur, a complicated course of the disease will eventually lead to serious kidney damage. The morphological examination of the renal biopsy aspirate is the only reliable mean to assess the nature of the glomerular changes and to make adequate therapeutic decisions.
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27
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Kreepala C, Panpruang P, Yodprom R, Piyajarawong T, Wattanavaekin K, Danjittrong T, Phuthomdee S. Manifestation of rs1888747 polymorphisms in the FRMD3 gene in diabetic kidney disease and diabetic retinopathy in type 2 diabetes patients. Kidney Res Clin Pract 2021; 40:263-271. [PMID: 34162050 PMCID: PMC8237118 DOI: 10.23876/j.krcp.20.190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/14/2021] [Indexed: 11/25/2022] Open
Abstract
Background FRMD3 polymorphisms has suggested that they could be an alternative test to differentiate diabetic nephropathy (DN) from nondiabetic renal disease (NDRD) in type 2 diabetes mellitus (DM) patients. This study was performed to investigate the relationship between the FRMD3 gene and clinical characteristics of DN. Methods Patients who already had renal pathologic results were tested for FRMD3 polymorphisms. The subjects were classified into three groups; DN with diabetic retinopathy (DR), DN without DR, and DM with NDRD. FRMD3 polymorphisms were analyzed in each group. Results The prevalence of GG, CG, and CC was 44.4%, 42.2%, and 13.3% respectively. There was no significant difference in clinical parameters, which consisted of disease duration, proteinuria, and complications in DN with or without DR and DM with NDRD. The G allele was mainly found in DN with DR patients (50.8%) whereas the C allele was found in DM with NDRD patients (43.5%) (p = 0.02). There was a significant association between the CC genotype in NDRD when compared to GG (p = 0.001). In addition, the C allele was 2.10-fold more often associated with NDRD than the G allele (p = 0.03). The CC genotype was correlated with risk for NDRD than the GG and GC genotypes, with odds ratios of 6.89 and 4.91, respectively (p = 0.02). Conclusion C allele presentation, especially homozygous CC, was associated with NDRD pathology in patients with overt proteinuria. Hence, kidney biopsy is suggested in those with the C allele or homozygous CC genotype, regardless of retinopathy manifestations.
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Affiliation(s)
- Chatchai Kreepala
- Nephrology Unit, School of Internal Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Pitirat Panpruang
- Department of Internal Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand
| | - Rapeeporn Yodprom
- Department of Ophthalmology, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand
| | - Teeraya Piyajarawong
- Department of Ophthalmology, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand
| | | | | | - Sadiporn Phuthomdee
- Department of Clinical Biostatistics, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Pak Kret, Thailand
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28
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Giandalia A, Giuffrida AE, Gembillo G, Cucinotta D, Squadrito G, Santoro D, Russo GT. Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors. Int J Mol Sci 2021; 22:5808. [PMID: 34071671 PMCID: PMC8198374 DOI: 10.3390/ijms22115808] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene-sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.
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Affiliation(s)
- Annalisa Giandalia
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy
| | - Domenico Cucinotta
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.E.G.); (G.G.); (D.S.)
| | - Giuseppina T. Russo
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (A.G.); (D.C.); (G.S.)
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29
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Genetic and Epigenomic Modifiers of Diabetic Neuropathy. Int J Mol Sci 2021; 22:ijms22094887. [PMID: 34063061 PMCID: PMC8124699 DOI: 10.3390/ijms22094887] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 12/18/2022] Open
Abstract
Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.
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30
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Kaur N, Singh IR, Vanita V. Association of Erythropoietin Gene Polymorphisms With Type 2 Diabetic Retinopathy in Adult Patients From Northern India. Can J Diabetes 2021; 45:785-791. [PMID: 34045145 DOI: 10.1016/j.jcjd.2021.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 08/03/2020] [Accepted: 03/26/2021] [Indexed: 12/21/2022]
Abstract
OBJECTIVES Our aim in this study was to determine the association of erythropoietin (EPO) gene polymorphisms with diabetic retinopathy in type 2 diabetes patients from northern India. METHODS In this case-control study, we recruited 614 participants, consisting of 302 diabetic retinopathy cases and 312 individuals with confirmed type 2 diabetes without retinopathy as controls. EPO polymorphism analysis was performed in all participants using polymerase chain reaction and direct DNA sequence analysis. RESULTS The genotype distribution and allele frequency of the c.246+265G>A (rs507392) polymorphism in differed significantly (p<0.05) between the retinopathy and control groups. For the -1306C>A (rs1617640) polymorphism, genotype distribution among the 2 groups analyzed differed significantly (p=0.047), but the distribution of allele frequency was not found to be statistically significant (p=0.07). For the c.∗772G>T (rs551238) variant, genotype distribution did not differ significantly when comparing the 2 groups (p=0.062), but allele frequency distribution did differ significantly (p=0.045). For the polymorphisms analyzed, namely rs507392 and rs1617640, a statistically significant association with retinopathy was observed (dominant model: adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.36 to 3.35; p<0.01; codominant model: adjusted OR, 1.45; 95% CI, 1.00 to 2.09; p=0.048). However, no significant association between c.∗772G>T (rs551238) polymorphism and diabetic retinopathy was found. CONCLUSIONS Our findings show 2 polymorphisms (c.246+265G>A [rs507392] and -1306C>A [rs1617640]) in EPO to be risk factors for type 2 diabetic retinopathy in a northern Indian cohort. To our knowledge, this is the first report from India to demonstrate an association between EPO gene polymorphisms and retinopathy.
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Affiliation(s)
- Navdeep Kaur
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Indu R Singh
- Dr. Daljit Singh Eye Hospital, Amritsar, Punjab, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India.
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Xiao H, Xu Y. Overexpression of Apolipoprotein C1 (APOC1) in Clear Cell Renal Cell Carcinoma and Its Prognostic Significance. Med Sci Monit 2021; 27:e929347. [PMID: 33591959 PMCID: PMC7896428 DOI: 10.12659/msm.929347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background The aims of this study included 3 aspects: 1) assessing the expression of Apolipoprotein C1 (APOC1) in clear cell renal cell carcinoma (ccRCC) and normal groups; 2) evaluating the prognostic significance of APOC1 expression in the overall survival (OS) of ccRCC patients; and 3) exploring APOC1-related signaling pathways. Material/Methods The APOC1 expression value and clinical data of ccRCC patients were obtained from the cBioPortal database. We then evaluated the association of APOC1 expression with clinical characteristics of ccRCC patients. We also assessed the correlation between APOC1 expression and clinical outcome using Kaplan-Meier method. Our work then verified the independent prognostic factors of ccRCC by Cox regression analysis. Finally, the potential role of genes co-expressed with APOC1 was revealed via functional enrichment analysis. Results Bioinformatic data revealed that APOC1 was expressed at higher levels in ccRCC tissue than in the normal group (all P<0.05). The high expression of APOC1 was associated with unfavorable prognosis of female patients (P<0.01), but not of male patients. APOC1 high expression also shortened the survival time of ccRCC patients age ≥60 years old (P<0.05). Cox regression analysis further indicated that APOC1 expression was an independent prognostic factor for OS of ccRCC patients. Additionally, we found that APOC1 expression was significantly associated with sex, grade, clinical stage, and T stage. Finally, enrichment analysis suggested that APOC1-associated pathways were involved in tumor growth and metastasis. Conclusions The current study indicated that APOC1 was highly expressed in ccRCC and was significantly associated with key clinical features. APOC1 appears to be an independent prognostic factor in patients with ccRCC. Importantly, APOC1 might be a potential therapeutic target for ccRCC via regulating pathways involved in cell growth and metastasis.
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Affiliation(s)
- Huaying Xiao
- Department of Nephrology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Yifang Xu
- Department of Nephrology, Dongyang People's Hospital, Dongyang, Zhejiang, China (mainland)
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Haghani A, Thorwald M, Morgan TE, Finch CE. The APOE gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans. Alzheimers Dement 2021; 17:175-190. [PMID: 33215813 PMCID: PMC7914175 DOI: 10.1002/alz.12230] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022]
Abstract
Little is known of gene-environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E (APOE) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the APOE network, air pollution, and age-related diseases. Mice exposed to air pollution nano-sized particulate matter (nPM) had coordinate responses of Apoe-Apoc1-Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in APOE cluster expression than the AD-resistant cerebellum and hypothalamus. Using consensus weighted gene co-expression network, we showed that APOE has a conserved co-expressed network in rodent and primate brains. SOX1, which has AD-associated single nucleotide polymorphisms, was among the co-expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in APOE cluster promoter, suggesting similar inducibility and a novel link among environment, APOE cluster, and risk of AD.
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Affiliation(s)
- Amin Haghani
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Max Thorwald
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Todd E Morgan
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Caleb E Finch
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
- Dornsife College, University of Southern California, Los Angeles, CA
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Khoo CM, Deerochanawong C, Chan SP, Matawaran B, Sheu WH, Chan J, Mithal A, Luk A, Suastika K, Yoon K, Ji L, Man NH, Pollock C. Use of sodium-glucose co-transporter-2 inhibitors in Asian patients with type 2 diabetes and kidney disease: An Asian perspective and expert recommendations. Diabetes Obes Metab 2021; 23:299-317. [PMID: 33155749 PMCID: PMC7839543 DOI: 10.1111/dom.14251] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/17/2020] [Accepted: 11/01/2020] [Indexed: 12/14/2022]
Abstract
Early onset of type 2 diabetes and a high prevalence of co-morbidities predispose the Asian population to a high risk for, and rapid progression of, diabetic kidney disease (DKD). Apart from renin-angiotensin system inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to delay renal disease progression in patients with DKD. In this review article, we consolidate the existing literature on SGLT-2 inhibitor use in Asian patients with DKD to establish contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, data from studies on Asian patients with DKD, global trials (DAPA-CKD, CREDENCE and DELIGHT) and cardiovascular outcomes trials. In patients with DKD, SGLT-2 inhibitor therapy significantly reduced albuminuria and the risk of hard renal outcomes (defined as the onset of end-stage kidney disease, substantial decline in renal function from baseline and renal death), cardiovascular outcomes and hospitalization for heart failure. In all the cardiovascular and renal outcomes trials, there was an initial decline in the estimated glomerular filtration rate (eGFR), which was followed by a slowing in the decline of renal function compared with that seen with placebo. Despite an attenuation in glucose-lowering efficacy in patients with low eGFR, there were sustained reductions in body weight and blood pressure, and an increase in haematocrit. Based on the available evidence, we conclude that SGLT-2 inhibitors represent an evidence-based therapeutic option for delaying the progression of renal disease in Asian patients with DKD and preserving renal function in patients at high risk of kidney disease.
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Affiliation(s)
| | | | - Siew Pheng Chan
- Department of MedicineUniversity of Malaya Medical CenterKuala LumpurMalaysia
| | - Bien Matawaran
- Department of Medicine, Section of Endocrinology, Diabetes and MetabolismUniversity of Santo Tomas HospitalManilaPhilippines
| | - Wayne Huey‐Herng Sheu
- Division of Endocrinology and Metabolism, Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan
| | - Juliana Chan
- Department of Medicine and TherapeuticsHong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales HospitalHong Kong
| | | | - Andrea Luk
- Department of Medicine and TherapeuticsHong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales HospitalHong Kong
| | - Ketut Suastika
- Faculty of MedicineUdayana University, Sanglah General HospitalBaliIndonesia
| | - Kun‐Ho Yoon
- Department of Endocrinology & Metabolism, Seoul St Maryʼs HospitalThe Catholic University of KoreaSeoulSouth Korea
| | - Linong Ji
- Peking University Peopleʼs HospitalPekingChina
| | | | - Carol Pollock
- The University of Sydney School of MedicineSydneyNew South WalesAustralia
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Darmayanti S, Lesmana R, Meiliana A, Abdulah R. Genomics, Proteomics and Metabolomics Approaches for Predicting Diabetic Nephropathy in Type 2 Diabetes Mellitus Patients. Curr Diabetes Rev 2021; 17:e123120189796. [PMID: 33393899 DOI: 10.2174/1573399817666210101105253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND There is a continuous rise in the prevalence of type 2 diabetes mellitus (T2DM) worldwide and most patients are unaware of the presence of this chronic disease at the early stages. T2DM is associated with complications related to long-term damage and failure of multiple organ systems caused by vascular changes associated with glycated end products, oxidative stress, mild inflammation, and neovascularization. Among the most frequent complications of T2DM observed in about 20-40% of T2DM patients is diabetes nephropathy (DN). METHODS A literature search was made in view of highlighting the novel applications of genomics, proteomics and metabolomics, as the new prospective strategy for predicting DN in T2DM patients. RESULTS The complexity of DN requires a comprehensive and unbiased approach to investigate the main causes of disease and identify the most important mechanisms underlying its development. With the help of evolving throughput technology, rapidly evolving information can now be applied to clinical practice. DISCUSSION DN is also the leading cause of end-stage renal disease and comorbidity independent of T2DM. In terms of the comorbidity level, DN has many phenotypes; therefore, timely diagnosis is required to prevent these complications. Currently, urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are gold standards for assessing glomerular damage and changes in renal function. However, GFR estimation based on creatinine is limited to hyperfiltration status; therefore, this makes albuminuria and eGFR indicators less reliable for early-stage diagnosis of DN. CONCLUSION The combination of genomics, proteomics, and metabolomics assays as suitable biological systems can provide new and deeper insights into the pathogenesis of diabetes, as well as discover prospects for developing suitable and targeted interventions.
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Affiliation(s)
- Siska Darmayanti
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Ronny Lesmana
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Anna Meiliana
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Rizky Abdulah
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
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Sol M, Kamps JAAM, van den Born J, van den Heuvel MC, van der Vlag J, Krenning G, Hillebrands JL. Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases. Front Pharmacol 2020; 11:573557. [PMID: 33123011 PMCID: PMC7573930 DOI: 10.3389/fphar.2020.573557] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 09/14/2020] [Indexed: 12/20/2022] Open
Abstract
Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk via intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.
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Affiliation(s)
- Marloes Sol
- Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jan A A M Kamps
- Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jacob van den Born
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Marius C van den Heuvel
- Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Guido Krenning
- Department of Pathology and Medical Biology, Division of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Cui Y, Miao C, Hou C, Wang Z, Liu B. Apolipoprotein C1 (APOC1): A Novel Diagnostic and Prognostic Biomarker for Clear Cell Renal Cell Carcinoma. Front Oncol 2020; 10:1436. [PMID: 32974161 PMCID: PMC7468425 DOI: 10.3389/fonc.2020.01436] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Apolipoprotein C1 (APOC1) has been proved to play a critical role in gastric, breast, lung, and pancreatic cancer. However, the relationship between APOC1 and urinary tumors remains unclear. This study aimed to assess the diagnostic and prognostic value of APOC1 in urinary tumors. Methods: We performed a pan analysis of APOC1 mRNA expression in urinary cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) database. To further investigate the prognostic value of APOC1 expression in urinary cancers, the Kaplan-Meier plotter database was used. Furthermore, we collected the tumor and adjacent normal samples of 32 ccRCC patients to perform qRT-PCR and western blotting assays. A total of 72 cases with ccRCC were analyzed using tissue microarrays (TMAs). Results: Our results based on Kaplan-Meier plotter database indicated that a high expression of APOC1 may lead to poor overall survival (OS, p = 0.0019) in patients with ccRCC. Furthermore, the cancer stages and tumor grade of ccRCC appeared to be strongly linked with APOC1 expression according to UALCAN database. Hence, we reached a preliminary conclusion that APOC1 may play a key role in the tumorigenesis and progression of ccRCC. Furthermore, the Kaplan-Meier survival curve analyses of 72 clinical patients indicated that high expression of APOC1 was associated with poor progression-free survival (PFS, p = 0.007) and OS (p = 0.022). In addition, univariate Cox regression analysis confirmed the significant relationship between APOC1 expression and survival (p = 0.038). The TMAs analysis in combination with the patients' clinicopathological features was also performed. The expression of APOC1 was found to be significantly correlated with the tumor size (p = 0.018) and histological grade (p = 0.016). Conclusions: In conclusion, the findings of our study suggest that APOC1 may serve as a novel diagnostic and prognostic biomarker for ccRCC. Further evidence on the mechanism of APOC1 promoting tumor progression may transform it to a new therapeutic target for the treatment of ccRCC.
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Affiliation(s)
- Yankang Cui
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chenkui Miao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chao Hou
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bianjiang Liu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Tziastoudi M, Stefanidis I, Zintzaras E. The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies. Clin Kidney J 2020; 13:768-781. [PMID: 33123356 PMCID: PMC7577775 DOI: 10.1093/ckj/sfaa077] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Indexed: 12/20/2022] Open
Abstract
Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.
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Affiliation(s)
- Maria Tziastoudi
- Department of Biomathematics, University of Thessaly, School of Medicine, Larissa, Greece
| | - Ioannis Stefanidis
- Department of Nephrology, University of Thessaly, School of Medicine, Larissa, Greece
| | - Elias Zintzaras
- Department of Biomathematics, University of Thessaly, School of Medicine, Larissa, Greece.,The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
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Jin J, Gong J, Zhao L, Li Y, Wang Y, He Q. iTRAQ-based comparative proteomics analysis reveals specific urinary biomarkers for various kidney diseases. Biomark Med 2020; 14:839-854. [PMID: 32856461 DOI: 10.2217/bmm-2019-0556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Proteome studies for multiple renal diseases is bare. Methodology & results: Using isobaric tags for relative and absolute quantitation labeling, many differentially expressed proteins (DEPs) were identified in acute kidney injury (AKI), AKI + chronic kidney disease (CKD), diabetic CKD and nondiabetic CKD with or without IgA nephropathy (IgAN). Comparative analysis indicated that 34, 35, 17, 91 and 14 unique DEPs were found in AKI, AKI + CKD, CKD, diabetic CKD and nondiabetic CKD. Compared with nondiabetic CKD with IgAN, 47 unique DEPs were found in that without IgAN. Serum amyloid A1 (SAA1) and hepatocyte growth factor activator were unregulated in AKI and nondiabetic CKD without IgAN, respectively. Regenerating islet-derived protein 3-α (Reg3A) upregulation is associated with AKI and AKI + CKD patients. Conclusion: This research contributes to urinary biomarker discovery from multiple renal diseases.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
| | - Jianguang Gong
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
| | - Li Zhao
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
| | - Yiwen Li
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
| | - Yunguang Wang
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
| | - Qiang He
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, PR China
- Department of Nephrology, People's Hospital of Hangzhou Medical College, Zhejiang 310014, PR China
- Key Laboratory of Kidney Disease of Traditional Chinese Medicine in Zhejiang Province, Zhejiang 310014, PR China
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Abstract
Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.
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Affiliation(s)
- Joanne B Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA
| | - Jose C Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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40
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Fawzy MS, Abu AlSel BT, Al Ageeli E, Al-Qahtani SA, Abdel-Daim MM, Toraih EA. Long non-coding RNA MALAT1 and microRNA-499a expression profiles in diabetic ESRD patients undergoing dialysis: a preliminary cross-sectional analysis. Arch Physiol Biochem 2020; 126:172-182. [PMID: 30270667 DOI: 10.1080/13813455.2018.1499119] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 07/08/2018] [Indexed: 01/22/2023]
Abstract
Background: Circulating non-coding RNAs (ncRNAs) have been implicated in health and disease. This study aimed to evaluate the serum expression profile of microRNA-499a (miR-499a) and its selected bioinformatically predicted partner long-ncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) in diabetes-related end-stage renal disease (ESRD) patients and to correlate the expressions with the patients' clinicolaboratory data.Subjects and methods: Real-time quantitative polymerase chain reaction was applied in diabetics with and without ESRD (n = 90 for each).Results: Serum MALAT1 expression levels were increased in the ESRD group relative to diabetics without ESRD with median (quartile) values of 10.5 (1.41-126.7) (p < .001). However, miR-499a levels were decreased in more than half of ESRD patients with a median of 0.96 (0.13-3.14). Both MALAT1 and miR-499a expression levels were inversely correlated in the ESRD patient-group.Conclusions: MALAT1 up-regulation and miR-499 down-regulation might be involved in diabetic nephropathy-related ESRD pathogenesis. Functional validation studies are warranted to confirm the MALAT1/miR-499a partnership.
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MESH Headings
- Adult
- Aged
- Base Pairing
- Base Sequence
- Cross-Sectional Studies
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/therapy
- Diabetic Nephropathies/diagnosis
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/genetics
- Diabetic Nephropathies/therapy
- Disease Progression
- Female
- Gene Expression Regulation
- Humans
- Kidney Failure, Chronic/diagnosis
- Kidney Failure, Chronic/etiology
- Kidney Failure, Chronic/genetics
- Kidney Failure, Chronic/therapy
- Male
- MicroRNAs/blood
- MicroRNAs/genetics
- Middle Aged
- RNA, Long Noncoding/blood
- RNA, Long Noncoding/genetics
- Renal Dialysis
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Affiliation(s)
- Manal S Fawzy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Baraah T Abu AlSel
- Department of Microbiology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Essam Al Ageeli
- Department of Clinical Biochemistry (Medical Genetics), Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | - Saeed Awad Al-Qahtani
- Department of Physiology, Faculty of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Eman A Toraih
- Department of Histology and Cell Biology (Genetics Unit), Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Center of Excellence of Molecular and Cellular Medicine, Suez Canal University, Ismailia, Egypt
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Regine I, Husain RSRA, Aswathi RP, Reddy DR, Ahmed SSSJ, Ramakrishnan V. Association between PPARγrs1801282 polymorphism with diabetic nephropathy and type-2 diabetes mellitus susceptibility in south India and a meta-analysis. Nefrologia 2020; 40:287-298. [PMID: 32417009 DOI: 10.1016/j.nefro.2020.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 12/19/2019] [Accepted: 01/19/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Diabetic Nephropathy (DN) is a major complication of Type 2 Diabetes Mellitus (T2DM) with high morbidity rates worldwide. OBJECTIVE To determine the association of PPARγ rs1801282 polymorphism in T2DM and DN in south Indian population. METHODS We have conducted a case-control study to test the association of rs1801282 polymorphism with T2DM and DN in 424 subjects (DN=128; T2DM=148 and controls=148) belonging to the south Indian population using ARMS-PCR and Sanger sequencing method. Further, a meta-analysis was performed for rs1801282 polymorphism from the published literature retrieved from various electronic databases to determine the susceptibility among T2DM and DN across various ethnic populations under five genetic models. RESULTS The genotyping of rs1801282 polymorphism showed significant (p-value<0.05) association with DN and T2DM compared to controls. In the meta-analysis, no significant association (p-value>0.05) was noticed for rs1801282 with DN vs. controls in homozygote, heterozygote, allelic, recessive and dominant genetic models. However, a significant association was observed between rs1801282 SNP and T2DM under heterozygote (Jj vs JJ) genetic model with OR=0.56, (95%CI [0.43-0.74]), p≤0.0001 of Asian and Caucasian populations. CONCLUSION Overall analysis suggests that the rs1801282 polymorphism might be associated with DN and T2DM. More case-control studies on the PPARγ gene with a larger sample size including all the confounding factors are required to corroborate the findings from this meta-analysis.
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Affiliation(s)
- Ilibagiza Regine
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | | | - Rajagopalan P Aswathi
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | - D Ramacharan Reddy
- Department of General Medicine, Chettinad Hospital and Research Institute, Chettinad Health City, Kelambakkam, Tamil Nadu, India
| | - Shiek S S J Ahmed
- Drug Discovery Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | - Veerabathiran Ramakrishnan
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India.
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Regine I, Husain RSRA, Aswathi RP, Reddy DR, Ahmed SSSJ, Ramakrishnan V. Association between PPARγrs1801282 polymorphism with diabetic nephropathy and type-2 diabetes mellitus susceptibility in south India and a meta-analysis. Nefrologia 2020; 40:287-298. [PMID: 32417009 DOI: 10.1016/j.nefroe.2020.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 12/19/2019] [Accepted: 01/19/2020] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Diabetic Nephropathy (DN) is a major complication of Type 2 Diabetes Mellitus (T2DM) with high morbidity rates worldwide. OBJECTIVE To determine the association of PPARγ rs1801282 polymorphism in T2DM and DN in south Indian population. METHODS We have conducted a case-control study to test the association of rs1801282 polymorphism with T2DM and DN in 424 subjects (DN=128; T2DM=148 and controls=148) belonging to the south Indian population using ARMS-PCR and Sanger sequencing method. Further, a meta-analysis was performed for rs1801282 polymorphism from the published literature retrieved from various electronic databases to determine the susceptibility among T2DM and DN across various ethnic populations under five genetic models. RESULTS The genotyping of rs1801282 polymorphism showed significant (p-value<0.05) association with DN and T2DM compared to controls. In the meta-analysis, no significant association (p-value>0.05) was noticed for rs1801282 with DN vs. controls in homozygote, heterozygote, allelic, recessive and dominant genetic models. However, a significant association was observed between rs1801282 SNP and T2DM under heterozygote (Jj vs JJ) genetic model with OR=0.56, (95%CI [0.43-0.74]), p≤0.0001 of Asian and Caucasian populations. CONCLUSION Overall analysis suggests that the rs1801282 polymorphism might be associated with DN and T2DM. More case-control studies on the PPARγ gene with a larger sample size including all the confounding factors are required to corroborate the findings from this meta-analysis.
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Affiliation(s)
- Ilibagiza Regine
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | | | - Rajagopalan P Aswathi
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | - D Ramacharan Reddy
- Department of General Medicine, Chettinad Hospital and Research Institute, Chettinad Health City, Kelambakkam, Tamil Nadu, India
| | - Shiek S S J Ahmed
- Drug Discovery Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | - Veerabathiran Ramakrishnan
- Genetics Lab, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India.
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Trout AL, Rutkai I, Biose IJ, Bix GJ. Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia. Int J Mol Sci 2020; 21:E679. [PMID: 31968632 PMCID: PMC7013765 DOI: 10.3390/ijms21020679] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/09/2020] [Accepted: 01/16/2020] [Indexed: 01/10/2023] Open
Abstract
Perlecan is a heparan sulfate proteoglycan protein in the extracellular matrix that structurally and biochemically supports the cerebrovasculature by dynamically responding to changes in cerebral blood flow. These changes in perlecan expression seem to be contradictory, ranging from neuroprotective and angiogenic to thrombotic and linked to lipid retention. This review investigates perlecan's influence on risk factors such as diabetes, hypertension, and amyloid that effect Vascular contributions to Cognitive Impairment and Dementia (VCID). VCID, a comorbidity with diverse etiology in sporadic Alzheimer's disease (AD), is thought to be a major factor that drives the overall clinical burden of dementia. Accordingly, changes in perlecan expression and distribution in response to VCID appears to be injury, risk factor, location, sex, age, and perlecan domain dependent. While great effort has been made to understand the role of perlecan in VCID, additional studies are needed to increase our understanding of perlecan's role in health and in cerebrovascular disease.
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Affiliation(s)
- Amanda L. Trout
- Department of Neurology, University of Kentucky, Lexington, KY 40536, USA;
| | - Ibolya Rutkai
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA 70112, USA; (I.R.); (I.J.B.)
- Tulane Brain Institute, Tulane University, New Orleans, LA 70118, USA
| | - Ifechukwude J. Biose
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA 70112, USA; (I.R.); (I.J.B.)
| | - Gregory J. Bix
- Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA 70112, USA; (I.R.); (I.J.B.)
- Tulane Brain Institute, Tulane University, New Orleans, LA 70118, USA
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Hsieh AR, Huang YC, Yang YF, Lin HJ, Lin JM, Chang YW, Wu CM, Liao WL, Tsai FJ. Lack of association of genetic variants for diabetic retinopathy in Taiwanese patients with diabetic nephropathy. BMJ Open Diabetes Res Care 2020; 8:8/1/e000727. [PMID: 31958309 PMCID: PMC7039583 DOI: 10.1136/bmjdrc-2019-000727] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 12/11/2019] [Accepted: 01/04/2020] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Diabetic nephropathy (DN) and diabetic retinopathy (DR) comprise major microvascular complications of diabetes that occur with a high concordance rate in patients and are considered to potentially share pathogeneses. In this case-control study, we sought to investigate whether DR-related single nucleotide polymorphisms (SNPs) exert pleiotropic effects on renal function outcomes among patients with diabetes. RESEARCH DESIGN AND METHODS A total of 33 DR-related SNPs were identified by replicating published SNPs and via a genome-wide association study. Furthermore, we assessed the cumulative effects by creating a weighted genetic risk score and evaluated the discriminatory and prediction ability of these genetic variants using DN cases according to estimated glomerular filtration rate (eGFR) status along with a cohort with early renal functional decline (ERFD). RESULTS Multivariate logistic regression models revealed that the DR-related SNPs afforded no individual or cumulative genetic effect on the nephropathy risk, eGFR status or ERFD outcome among patients with type two diabetes in Taiwan. CONCLUSION Our findings indicate that larger studies would be necessary to clearly ascertain the effects of individual genetic variants and further investigation is also required to identify other genetic pathways underlying DN.
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Affiliation(s)
- Ai-Ru Hsieh
- Department of Statistics, Tamkang University, Taipei, Taiwan
| | - Yu-Chuen Huang
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ya-Fei Yang
- Kidney Institute and Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hui-Ju Lin
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan
| | - Jane-Ming Lin
- Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan
| | - Ya-Wen Chang
- Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Ming Wu
- Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Ling Liao
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Fuu-Jen Tsai
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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Fuior EV, Gafencu AV. Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond. Int J Mol Sci 2019; 20:ijms20235939. [PMID: 31779116 PMCID: PMC6928722 DOI: 10.3390/ijms20235939] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/19/2019] [Accepted: 11/21/2019] [Indexed: 12/20/2022] Open
Abstract
Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and-not last-to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.
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Affiliation(s)
- Elena V. Fuior
- Institute of Cellular Biology and Pathology “N. Simionescu”, 050568 Bucharest, Romania;
| | - Anca V. Gafencu
- Institute of Cellular Biology and Pathology “N. Simionescu”, 050568 Bucharest, Romania;
- Correspondence:
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Wang Y, Tan J, Liu D, Yang Y, Wu H. The Association of UNC13B Gene Polymorphisms and Diabetic Kidney Disease in a Chinese Han Population. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2019; 25:8527-8533. [PMID: 31713534 PMCID: PMC6865244 DOI: 10.12659/msm.919930] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Polymorphisms in the UNC13B gene are associated with diabetic kidney disease (DKD) in the European population. Asian populations are more likely to suffer from complications of type 2 diabetes mellitus (T2DM), including diabetic kidney disease (DKD). This case-control study aimed to investigate the association between UNC13B gene polymorphisms and DKD in a Chinese Han population. MATERIAL AND METHODS Five single nucleotide polymorphism (SNP) loci (rs13293564, rs17360668, rs10114937, rs661712, and rs2281999) were genotyped in the UNC13B gene in 600 Chinese Han subjects. The study population included patients with T2DM with DKD (N=292) and control patients with T2DM without DKD (N=308). SNP genotyping was performed using a Sequenom MassARRAY system using chip-based matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). RESULTS There were no significant differences in the distribution of allele or genotype frequencies in the five UNC13B SNP markers (rs13293564, rs17360668, rs10114937, rs661712, and rs2281999) between the DKD group and control group of patients with T2DM. Haplotype analysis identified eight haplotypes for the combined effect of the five SNP markers in the UNC13B gene. The haplotype GGCCG was significantly associated with an increased risk of DKD. CONCLUSIONS This was the first study to demonstrate an association between UNC13B gene polymorphisms and the susceptibility to DKD in a Chinese Han population with T2DM. The haplotype GGCCG was significantly associated with an increased risk of DKD. The findings highlight the joint effect of SNP markers in the pathogenesis of DKD.
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Affiliation(s)
- Ya Wang
- Department of Endocrinology, Jingzhou First People's Hospital, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China (mainland)
| | - Jie Tan
- Department of Hematology, Jingzhou First People's Hospital, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China (mainland)
| | - Dan Liu
- Department of Endocrinology, Jingzhou First People's Hospital, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China (mainland)
| | - Yameng Yang
- Department of Rheumatism and Immunology, Jingzhou First People's Hospital, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China (mainland)
| | - Hongyan Wu
- Department of Endocrinology, Jingzhou First People's Hospital, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China (mainland)
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Schmöhl F, Peters V, Schmitt CP, Poschet G, Büttner M, Li X, Weigand T, Poth T, Volk N, Morgenstern J, Fleming T, Nawroth PP, Kroll J. CNDP1 knockout in zebrafish alters the amino acid metabolism, restrains weight gain, but does not protect from diabetic complications. Cell Mol Life Sci 2019; 76:4551-4568. [PMID: 31073745 PMCID: PMC11105213 DOI: 10.1007/s00018-019-03127-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 04/22/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
The gene CNDP1 was associated with the development of diabetic nephropathy. Its enzyme carnosinase 1 (CN1) primarily hydrolyzes the histidine-containing dipeptide carnosine but other organ and metabolic functions are mainly unknown. In our study we generated CNDP1 knockout zebrafish, which showed strongly decreased CN1 activity and increased intracellular carnosine levels. Vasculature and kidneys of CNDP1-/- zebrafish were not affected, except for a transient glomerular alteration. Amino acid profiling showed a decrease of certain amino acids in CNDP1-/- zebrafish, suggesting a specific function for CN1 in the amino acid metabolisms. Indeed, we identified a CN1 activity for Ala-His and Ser-His. Under diabetic conditions increased carnosine levels in CNDP1-/- embryos could not protect from respective organ alterations. Although, weight gain through overfeeding was restrained by CNDP1 loss. Together, zebrafish exhibits CN1 functions, while CNDP1 knockout alters the amino acid metabolism, attenuates weight gain but cannot protect organs from diabetic complications.
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Affiliation(s)
- Felix Schmöhl
- European Center for Angioscience (ECAS), Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Verena Peters
- Center for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
| | - Claus Peter Schmitt
- Center for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
| | - Gernot Poschet
- Center for Organismal Studies (COS), University of Heidelberg, Im Neuenheimer Feld 360, 69120, Heidelberg, Germany
| | - Michael Büttner
- Center for Organismal Studies (COS), University of Heidelberg, Im Neuenheimer Feld 360, 69120, Heidelberg, Germany
| | - Xiaogang Li
- European Center for Angioscience (ECAS), Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany
| | - Tim Weigand
- Center for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
| | - Tanja Poth
- CMCP-Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Nadine Volk
- Tissue Bank of the National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Jakob Morgenstern
- Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Thomas Fleming
- Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Peter P Nawroth
- Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, München, Im Neuenheimer Feld 410, F02 Room 02.414-02.434, 69120, Heidelberg, Germany
| | - Jens Kroll
- European Center for Angioscience (ECAS), Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany.
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Kallinikou D, Soldatou A, Tsentidis C, Louraki M, Kanaka-Gantenbein C, Kanavakis E, Karavanaki K. Diabetic neuropathy in children and adolescents with type 1 diabetes mellitus: Diagnosis, pathogenesis, and associated genetic markers. Diabetes Metab Res Rev 2019; 35:e3178. [PMID: 31083769 DOI: 10.1002/dmrr.3178] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 04/10/2019] [Accepted: 05/07/2019] [Indexed: 01/09/2023]
Abstract
Diabetic neuropathy (DN) is a common long-term complication of type 1 (T1D) and type 2 (T2D) diabetes mellitus, with significant morbidity and mortality. DN is defined as impaired function of the autonomic and/or peripheral nervous system, often subclinical, particularly in children and adolescents with T1D. Nerve conduction studies (NCS) and skin biopsies are considered gold-standard methods in the assessment of DN. Multiple environmental and genetic factors are involved in the pathogenesis of DN. Specifically, the role of metabolic control and glycemic variability is of paramount importance. A number of recently identified genes, including the AKR1B1, VEGF, MTHFR, APOE, and ACE genes, contribute significantly in the pathogenesis of DN. These genes may serve as biomarkers to predict future DN development or treatment response. In addition, they may serve as the basis for the development of new medications or gene therapy. In this review, the diagnostic evaluation, pathogenesis, and associated genetic markers of DN in children and adolescents with T1D are presented and discussed.
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Affiliation(s)
- Dimitra Kallinikou
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
| | - Alexandra Soldatou
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
| | - Charalambos Tsentidis
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
| | - Maria Louraki
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
| | - Christina Kanaka-Gantenbein
- Diabetes Center, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Emmanouil Kanavakis
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
- Department of Medical Genetics, Choremeio Research Laboratory, National and Kapodistrian University of Athens, Athens, Greece
| | - Kyriaki Karavanaki
- Diabetes and Metabolism Clinic, 2nd Department of Pediatrics, National and Kapodistrian University of Athens-Faculty of Medicine, "P.&A. Kyriakou" Children's Hospital, Athens, Greece
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Cantarelli C, Angeletti A, Cravedi P. Erythropoietin, a multifaceted protein with innate and adaptive immune modulatory activity. Am J Transplant 2019; 19:2407-2414. [PMID: 30903735 PMCID: PMC6711804 DOI: 10.1111/ajt.15369] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/14/2019] [Accepted: 03/16/2019] [Indexed: 01/25/2023]
Abstract
Erythropoietin (EPO) is a glycoprotein produced mainly by the adult kidney in response to hypoxia and is the crucial regulator of red blood cell production. EPO receptors (EPORs), however, are not confined to erythroid cells, but are expressed by many organs including the heart, brain, retina, pancreas, and kidney, where they mediate EPO-induced, erythropoiesis-independent, tissue-protective effects. Some of these tissues also produce and locally release small amounts of EPO in response to organ injury as a mechanism of self-repair. Growing evidence shows that EPO possesses also important immune-modulating effects. Monocytes can produce EPO, and autocrine EPO/EPOR signaling in these cells is crucial in maintaining immunologic self-tolerance. New data in mice and humans also indicate that EPO has a direct inhibitory effect on effector/memory T cells, while it promotes formation of regulatory T cells. This review examines the nonerythropoietic effects of EPO, with a special emphasis on its modulating activity on innate immune cells and T cells and on how it affects transplant outcomes.
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Affiliation(s)
- Chiara Cantarelli
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Andrea Angeletti
- Department of Experimental, Diagnostic, Specialty Medicine, Nephrology, Dialysis, and Renal Transplant Unit, S. Orsola University Hospital, Bologna, Italy
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program. Nat Commun 2019; 10:3842. [PMID: 31451708 PMCID: PMC6710266 DOI: 10.1038/s41467-019-11704-w] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.
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