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Zheng J, Manabe Y, Sugawara T. Preventive effect of siphonaxanthin, a carotenoid from green algae, against diabetic nephropathy and lipid metabolism insufficiency in skeletal muscle. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159604. [PMID: 39986648 DOI: 10.1016/j.bbalip.2025.159604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
Diabetic nephropathy is a complication of diabetes mellitus characterized by the gradual progression of renal insufficiency, resulting in renal failure. Approximately 15 % or more of patients with type 2 diabetes mellitus have diabetic nephropathy. Siphonaxanthin is a green algal carotenoid noted for its strong biological activities, including anti-obesity effects. In this study, we aimed to evaluate the preventive effects of siphonaxanthin on diabetic nephropathy using db/db mice as a type 2 diabetes mellitus and diabetic nephropathy model. Ingestion of AIN-93G containing 0.004 % w/w siphonaxanthin did not improve plasma creatinine and urine albumin levels but significantly mitigated renal morphological changes in diabetic mice. Moreover, siphonaxanthin restored the decreased mRNA expression of fatty acid β-oxidation-related proteins in the skeletal muscle. These results indicate that siphonaxanthin can potentially ameliorate type 2 diabetes mellitus-induced kidney damage and lipid metabolism insufficiency in skeletal muscle. This study provides a possible daily nutraceutical solution for treating diabetic nephropathy and lipid metabolic abnormalities.
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Affiliation(s)
- Jiawen Zheng
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University. Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan
| | - Yuki Manabe
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University. Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
| | - Tatsuya Sugawara
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University. Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
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Rosas-Martínez L, Rodríguez-Muñoz R, Namorado-Tonix MDC, Missirlis F, Del Valle-Mondragón L, Sánchez-Mendoza A, Reyes-Sánchez JL, Cervantes-Pérez LG. Peroxisome Proliferator-Activated Receptor Alpha Stimulation Preserves Renal Tight Junction Components in a Rat Model of Early-Stage Diabetic Nephropathy. Int J Mol Sci 2024; 25:13152. [PMID: 39684861 DOI: 10.3390/ijms252313152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Chronic hyperglycemia results in morphological and functional alterations of the kidney and microvascular damage, leading to diabetic nephropathy (DN). Since DN progresses to irreversible renal damage, it is important to elucidate a pharmacological strategy aimed for treating DN in the early stage. Here, we used the type 2 diabetic rat model to induce DN and show a nephroprotective effect following the stimulation of PPAR-α, which stabilized renal tight junction components claudin-2, claudin-5, and claudin-16. At 14 weeks old, streptozotocin-induced DN, evidenced by elevated creatinine clearance, proteinuria, and electrolyte excretion, was followed by an elevation in oxidative stress and increasing MMP activities affecting the integrity of claudin-2 and claudin-5. Treatment with a PPAR-α agonists decreased glucose levels in diabetic rats. In addition, we found that the expressions of CLDN-5 in glomeruli, CLDN-2 in proximal tubules, and CLDN-16 in the thick ascending limb of the loop of Henle were increased after treatment. As a result, renal function improved, while the oxidative stress and enzymatic activity of MMP-2 and MMP-9 decreased. In conclusion, PPAR-α stimulation prevented the decrease in claudins through a mechanism involving a correction of hyperglycemia, decreasing it in kidney oxidative stress and MMP-2 and MMP-9 activities, showing a promising nephroprotective action in the early stage of DN.
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Affiliation(s)
- Lorena Rosas-Martínez
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Rafael Rodríguez-Muñoz
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - María Del Carmen Namorado-Tonix
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Fanis Missirlis
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Leonardo Del Valle-Mondragón
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
| | - Alicia Sánchez-Mendoza
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
| | - José L Reyes-Sánchez
- Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies of National Polytechnic Institute, CINVESTAV-IPN, Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Gustavo A. Madero, Mexico City 07360, Mexico
| | - Luz Graciela Cervantes-Pérez
- Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan, Mexico City 14080, Mexico
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Taurbekova B, Mukhtarova K, Salpynov Z, Atageldiyeva K, Sarria-Santamera A. The impact of PPARγ and ApoE gene polymorphisms on susceptibility to diabetic kidney disease in type 2 diabetes mellitus: a meta-analysis. BMC Nephrol 2024; 25:436. [PMID: 39614174 PMCID: PMC11607899 DOI: 10.1186/s12882-024-03859-6] [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: 08/07/2024] [Accepted: 11/14/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Globally, diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease, imposing substantial social and economic costs. This meta-analysis was designed to provide valuable insights into gene-disease interactions by investigating the potential association between lipid metabolism gene polymorphisms and the risk of DKD. METHODS An electronic literature search was conducted on MEDLINE Complete, Web of Science, Embase, and PubMed. A total of 18 studies on the peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala variant and 20 publications concerning apolipoprotein E (ApoE) gene polymorphism were included in the meta-analysis. RESULTS Overall, the PPARγ Pro12Ala polymorphism was found to be significantly associated with a decreased DKD risk (OR = 0.74, 95% CI: 0.62-0.88). In subgroup analysis, Ala carriers were less susceptible to DKD than Pro homozygotes among Asian (OR = 0.73, 95% CI: 0.56-0.95) and Caucasian populations (OR = 0.74, 95% CI: 0.59-0.93). Subgroup analysis stratified by albuminuria categories showed that the PPARγ Pro12Ala polymorphism reduced the risk of both microalbuminuria and macroalbuminuria with corresponding ORs of 0.58 (95% CI: 0.43-0.78) and 0.68 (95% CI: 0.53-0.86). Sensitivity analysis confirmed the robustness of the meta-analysis results. However, publication bias was identified in the subgroup analysis of the Caucasian population. The primary analysis of the ApoE gene polymorphism yielded significant findings, indicating that ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes increase the risk of DKD (ε2/ε2 vs. ε3/ε3: OR = 1.93, 95% CI: 1.03-3.61; ε2/ε3 vs. ε3/ε3: OR = 1.63, 95% CI: 1.19-2.25; ε2/ε4 vs. ε3/ε3: OR = 1.87, 95% CI: 1.37-2.55). However, sensitivity analysis suggested that influential and Hardy-Weinberg equilibrium (HWE)-violating studies may impact the overall effect estimates. CONCLUSIONS A meta-analysis showed that PPARγ gene polymorphism may be a protective factor for DKD, whereas the ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes are associated with an increased risk of DKD. However, the role of ApoE gene polymorphism in susceptibility to DKD is less certain and requires further evaluation.
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Affiliation(s)
- Binura Taurbekova
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan.
- School of Medicine, Nazarbayev University, 5/1 Kerey and Zhanibek Khandar Str, Astana city, Republic of Kazakhstan.
| | - Kymbat Mukhtarova
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Zhandos Salpynov
- Department of Surgery, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Kuralay Atageldiyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Antonio Sarria-Santamera
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan
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Jagdale AD, Angal MM, Patil RS, Tupe RS. Exploring the glycation association with dyslipidaemia: Novel approach for diabetic nephropathy. Biochem Pharmacol 2024; 229:116513. [PMID: 39218042 DOI: 10.1016/j.bcp.2024.116513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/14/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
The transcription factor known as sterol regulatory element-binding protein (SREBP) and the glycation pathways, specifically the formation of Advanced Glycation End Products (AGEs), have a significant and deleterious impact on the kidney. They alter renal lipid metabolism and promote glomerulosclerosis, mesangial cell expansion, tubulointerstitial fibrosis, and inflammation, leading to diabetic nephropathy (DN) progression. Although several pieces of scientific evidence are reported for potential causes of glycation and lipotoxicity in DN, the underlying mechanism of renal lipid accumulation still needs to be fully understood. We provide a rationalized view on how AGEs exert multiple effects that cause SREBP activation and inflammation, contributing to DN through Receptor for AGEs (RAGE) signaling, AGE-R1-dependent downregulation of Sirtuin 1 (SIRT-1), and increased SREBP Cleavage Activating Protein (SCAP) glycosylation. This review emphasizes the association between glycation and the SREBP pathway and how it affects the onset of DN associated with obesity. Finally, we discuss the correlation of glycation and the SREBP pathway with insulin resistance (IR), oxidative stress, endoplasmic reticulum stress, inflammation, and existing and emerging therapeutic approaches toward better controlling obesity-related DN.
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Affiliation(s)
- Ashwini D Jagdale
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India
| | - Mukul M Angal
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India
| | - Rahul S Patil
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Rashmi S Tupe
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, Maharashtra, India.
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Al Madhoun A. MicroRNA-630: A potential guardian against inflammation in diabetic kidney disease. World J Diabetes 2024; 15:1837-1841. [PMID: 39280181 PMCID: PMC11372643 DOI: 10.4239/wjd.v15.i9.1837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/20/2024] [Accepted: 06/17/2024] [Indexed: 08/27/2024] Open
Abstract
In this editorial, we comment on the article by Wu et al published "MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4". Diabetic kidney disease (DKD) stands as a significant complication occurring from diabetes mellitus, which contributes substantially to the morbidity and mortality rates worldwide. Renal tubular epithelial cell da-mage, often accompanied by inflammatory responses and mesenchymal trans-differentiation, plays a pivotal role in the progression of DKD. Despite extensive research, the intricate molecular mechanisms underlying these processes remain to be determined. Wu et al remarkable work identifies microRNA-630 (miR-630) as an emerging potential regulator of cell migration, apoptosis, and autophagy, prompting investigation into its association with DKD pathogenesis. This study endeavors to elucidate the impact of miR-630 on TEC injury and the inflammatory response in DKD rats. The role of miR-630 in human DKD will be of interest for future studies.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15400, Kuwait
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Wang Z, Zhang J, Jiao F, Wu Y, Han L, Jiang G. Genetic association analyses highlight apolipoprotein B as a determinant of chronic kidney disease in patients with type 2 diabetes. J Clin Lipidol 2024; 18:e787-e796. [PMID: 39278771 DOI: 10.1016/j.jacl.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND Blood lipid levels were associated with chronic kidney disease (CKD) in patients with type 2 diabetes (T2D), but the genetic basis and causal nature remain unclear. OBJECTIVE This study aimed to investigate the relationships of lipids and their fractions with CKD in patients with T2D. METHODS Our prospective analysis involved 8,607 White participants with T2D but no CKD at baseline from the UK Biobank. Five common lipid traits were included as exposures. Weighted genetic risk scores (GRSs) for these lipid traits were developed. The causal associations between lipid traits, as well as lipid fractions, and CKD were explored using linear or nonlinear Mendelian randomization (MR). The 10-year predicted probabilities of CKD were evaluated via integrating MR and Cox models. RESULTS Higher GRS of apolipoprotein B (ApoB) was associated with an increased CKD risk (hazard ratio (HR) [95% confidence interval (CI)]:1.07[1.02,1.13] per SD; P = 0.008) after adjusting for potential confounders. Linear MR indicated a positive association between genetically predicted ApoB levels and CKD (HR [95% CI]:1.53 [1.12,2.09]; P = 0.008), but no evidence of associations was found between other lipid traits and CKD in T2D. Regarding 12 ApoB- containing lipid fractions, a significant causal association was found between medium very-low-density lipoprotein particles and CKD (HR[95% CI]:1.16[1.02,1.32];P = 0.020). Nonlinear MR did not support nonlinearity in these causal associations. The 10-year probability curve showed that ApoB level was positively associated with the risk of CKD in patients with T2D. CONCLUSION Lower ApoB levels were causally associated with a reduced risk of CKD in patients with T2D, positioning ApoB as a potential therapeutic target for CKD prevention in this population.
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Affiliation(s)
- Zhenqian Wang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang)
| | - Jiaying Zhang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang)
| | - Feng Jiao
- Guangzhou Centre for Applied Mathematics, Guangzhou University, Guangzhou, China (Dr Jiao)
| | - Yueheng Wu
- Medical Research Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China (Dr Wu)
| | - Liyuan Han
- Department of Global Health, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China (Dr Han)
| | - Guozhi Jiang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China (Drs Wang, Zhang, Jiang); Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen, Guangdong, China (Dr Jiang).
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Mazzieri A, Porcellati F, Timio F, Reboldi G. Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection. Int J Mol Sci 2024; 25:3969. [PMID: 38612779 PMCID: PMC11012439 DOI: 10.3390/ijms25073969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/28/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.
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Affiliation(s)
- Alessio Mazzieri
- Diabetes Clinic, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (A.M.), (F.P.)
| | - Francesca Porcellati
- Diabetes Clinic, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (A.M.), (F.P.)
| | - Francesca Timio
- Division of Nephrology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
| | - Gianpaolo Reboldi
- Division of Nephrology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
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Xu S, Li X, Hou Q, Xu N, Lu Q, Wang S, Dai C. Association of Serum Unsaturated Fatty Acid Patterns with the Risk of Diabetic Nephropathy. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:97-106. [PMID: 38751794 PMCID: PMC11095590 DOI: 10.1159/000536532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/22/2024] [Indexed: 05/18/2024]
Abstract
Introduction Unsaturated fatty acids play an essential role in the progression of diabetic nephropathy (DN). However, previous studies were mainly focused on the role of individual unsaturated fatty acid. The serum unsaturated fatty acid patterns (FAPs) in patients with DN remain to be determined. Methods A total of 135 patients with DN (DN group) and 322 patients with type II diabetes without nephropathy (non-DN group) were included in this study. Clinical data, serum levels of unsaturated fatty acids, and other laboratory indicators were collected. Multivariate logistic regression was applied to identify risk factors for serum unsaturated fatty acid level in both groups. Serum unsaturated fatty acids were subjected to factor analysis to identify distinct FAPs. Multivariable logistic regression was employed to assess the risk of DN associated with different serum FAPs. Results After adjusting for confounders, three types of unsaturated fatty acid including C20:5 (eicosapentaenoic acid [EPA]), C22:6 (docosahexaenoic acid [DHA]), and C22:5 n-3 (docosapentaenoic acid n-3) were significantly associated with DN in the population. The odds ratios (ORs) (95% confidence interval [CI]) of DN were 0.583 (0.374, 0.908), 0.826 (0.716, 0.954), and 0.513 (0.298, 0.883), respectively. Factor analysis revealed five major FAPs, among which FAP2 (enriched with EPA and DHA) exhibited a significant inverse association with DN. In the multivariate-adjusted model, the OR (95% CI) was 0.678 (0.493, 0.933). Additionally, a combination of DHA and EPA enriched in FAP2 further decreased extracellular matrix production induced by transforming growth factor beta 1 in podocytes and tubular cells. Conclusions Our findings suggest that FAP2 which is enriched with DHA and EPA is associated with a reduced risk of DN. This highlights the potential of targeting FAP2 for the patients with DN.
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Affiliation(s)
- Shuang Xu
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyuan Li
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Hou
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ning Xu
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qingmiao Lu
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sudan Wang
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chunsun Dai
- Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Clinical Genetics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Bhattacharjee B, Chakrovorty A, Biswas M, Samadder A, Nandi S. To Explore the Putative Molecular Targets of Diabetic Nephropathy and their Inhibition Utilizing Potential Phytocompounds. Curr Med Chem 2024; 31:3752-3790. [PMID: 37211853 DOI: 10.2174/0929867330666230519112312] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/17/2023] [Accepted: 03/31/2023] [Indexed: 05/23/2023]
Abstract
BACKGROUND This review critically addresses the putative molecular targets of Diabetic Nephropathy (DN) and screens effective phytocompounds that can be therapeutically beneficial, and highlights their mechanistic modalities of action. INTRODUCTION DN has become one of the most prevalent complications of clinical hyperglycemia, with individual-specific variations in the disease spectrum that leads to fatal consequences. Diverse etiologies involving oxidative and nitrosative stress, activation of polyol pathway, inflammasome formation, Extracellular Matrix (ECM) modifications, fibrosis, and change in dynamics of podocyte functional and mesangial cell proliferation adds up to the clinical complexity of DN. Current synthetic therapeutics lacks target-specific approach, and is associated with the development of inevitable residual toxicity and drug resistance. Phytocompounds provides a vast diversity of novel compounds that can become an alternative therapeutic approach to combat the DN. METHODS Relevant publications were searched and screened from research databases like GOOGLE SCHOLAR, PUBMED and SCISEARCH. Out of 4895 publications, the most relevant publications were selected and included in this article. RESULT This study critically reviews over 60 most promising phytochemical and provides with their molecular targets, that can be of pharmacological significance in context to current treatment and concomitant research in DN. CONCLUSION This review highlights those most promising phytocompounds that have the potential of becoming new safer naturally-sourced therapeutic candidates and demands further attention at clinical level.
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Affiliation(s)
- Banani Bhattacharjee
- Endocrinology and Reproductive Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, 741235, West Bengal, India
| | - Arnob Chakrovorty
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, 741235, India
| | - Maharaj Biswas
- Endocrinology and Reproductive Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, 741235, West Bengal, India
| | - Asmita Samadder
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, 741235, India
| | - Sisir Nandi
- Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur, 244713, India
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Beniwal A, Jain JC, Jain A. Lipids: A Major Culprit in Diabetic Nephropathy. Curr Diabetes Rev 2024; 20:60-69. [PMID: 38018185 DOI: 10.2174/0115733998259273231101052549] [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: 05/12/2023] [Revised: 08/13/2023] [Accepted: 09/28/2023] [Indexed: 11/30/2023]
Abstract
The pathophysiology of diabetic nephropathy (DN) is too complex and involves a variety of pathways and mediators. Hyperglycaemia and dyslipidemia are identified as major risk factors for diabetic nephropathy. Various studies revealed the fact that dyslipidemia is a major contributor to the process of diabetic nephropathy. Dyslipidemia refers to abnormal lipid levels. Lipids like LDL, free fatty acids, abnormal lipoproteins, ceramides, etc., are unsafe for kidneys. They target proximal tubular epithelial cells, podocytes, and tubulointerstitial tissues through biochemical changes, especially by enhancing the release of reactive oxygen species (ROS) and lipid peroxidation, endorsing tissue inflammation and mitochondrial damage, which give rise to nephropathy. Major lipid targets identified are SREBP1, LXR, FXR PPAR, CD-36, PKc, AGE/RAGE pathway, and ferroptosis. The drug acting on these targets has shown improvement in DN patients. Various preclinical and clinical studies support the fact that hyperlipidemic agents are promising targets for DN. Therefore, in conjunction with other standard therapies, drugs acting on dyslipidemia can be added as a part of the regimen in order to prevent the incidence of ESRD and CVD.
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Affiliation(s)
- Ankita Beniwal
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Jasmine Chaudhary Jain
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Akash Jain
- College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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12
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Al Jadani JM, Albadr NA, Alshammari GM, Almasri SA, Alfayez FF, Yahya MA. Esculeogenin A, a Glycan from Tomato, Alleviates Nonalcoholic Fatty Liver Disease in Rats through Hypolipidemic, Antioxidant, and Anti-Inflammatory Effects. Nutrients 2023; 15:4755. [PMID: 38004149 PMCID: PMC10675668 DOI: 10.3390/nu15224755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
This study examined the preventative effects of esculeogenin A (ESGA), a newly discovered glycan from tomato, on liver damage and hepatic steatosis in high-fat-diet (HFD)-fed male rats. The animals were divided into six groups (each of eight rats): a control group fed a normal diet, control + ESGA (200 mg/kg), HFD, and HFD + ESAG in 3 doses (50, 100, and 200 mg/kg). Feeding and treatments were conducted for 12 weeks. Treatment with ESGA did not affect gains in the body or fat weight nor increases in fasting glucose, insulin, and HOMA-IR or serum levels of free fatty acids (FFAs), tumor-necrosis factor-α, and interleukin-6 (IL-6). On the contrary, it significantly reduced the serum levels of gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total triglycerides (TGs), cholesterol (CHOL), and low-density lipoprotein cholesterol (LDL-c) in the HFD-fed rats. In addition, it improved the liver structure, attenuating the increase in fat vacuoles; reduced levels of TGs and CHOL, and the mRNA levels of SREBP1 and acetyl CoA carboxylase (ACC); and upregulated the mRNA levels of proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase I (CPT I) in HFD-fed rats. These effects were concomitant with increases in the mRNA, cytoplasmic, and nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and heme oxygenase-1 (HO); a reduction in the nuclear activity of nuclear factor-kappa beta (NF-κB); and inhibition of the activity of nuclear factor kappa B kinase subunit beta (IKKβ). All of these effects were dose-dependent effects in which a normal liver structure and normal levels of all measured parameters were seen in HFD + ESGA (200 mg/kg)-treated rats. In conclusion, ESGA prevents NAFLD in HFD-fed rats by attenuating hyperlipidemia, hepatic steatosis, oxidative stress, and inflammation by acting locally on Nrf2, NF-κB, SREBP1, and PPARα transcription factors.
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Affiliation(s)
- Jwharah M. Al Jadani
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (J.M.A.J.); (G.M.A.); (S.A.A.); (M.A.Y.)
| | - Nawal A. Albadr
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (J.M.A.J.); (G.M.A.); (S.A.A.); (M.A.Y.)
| | - Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (J.M.A.J.); (G.M.A.); (S.A.A.); (M.A.Y.)
| | - Soheir A. Almasri
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (J.M.A.J.); (G.M.A.); (S.A.A.); (M.A.Y.)
| | - Farah Fayez Alfayez
- Department of Medicine and Surgery, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (J.M.A.J.); (G.M.A.); (S.A.A.); (M.A.Y.)
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13
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Xu K, Saaoud F, Shao Y, Lu Y, Wu S, Zhao H, Chen K, Vazquez-Padron R, Jiang X, Wang H, Yang X. Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis. Redox Biol 2023; 64:102771. [PMID: 37364513 PMCID: PMC10310484 DOI: 10.1016/j.redox.2023.102771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/24/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023] Open
Abstract
To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE-/- mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2-/- transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity.
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Affiliation(s)
- Keman Xu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Ying Shao
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Yifan Lu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Sheng Wu
- Metabolic Disease Research, Thrombosis Research, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Huaqing Zhao
- Medical Education and Data Science, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA
| | - Kaifu Chen
- Computational Biology Program, Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Roberto Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33125, USA
| | - Xiaohua Jiang
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA; Metabolic Disease Research, Thrombosis Research, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Hong Wang
- Metabolic Disease Research, Thrombosis Research, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA; Metabolic Disease Research, Thrombosis Research, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
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14
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He H, Zhong Y, Wang H, Tang PMK, Xue VW, Chen X, Chen J, Huang X, Wang C, Lan H. Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ. Int J Mol Sci 2023; 24:11396. [PMID: 37511155 PMCID: PMC10380492 DOI: 10.3390/ijms241411396] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.
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Affiliation(s)
- Huijun He
- Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Yu Zhong
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Honglian Wang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Patrick Ming-Kuen Tang
- State Key Laboratory of Translational Oncology, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Vivian Weiwen Xue
- State Key Laboratory of Translational Oncology, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Xiaocui Chen
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jiaoyi Chen
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Xiaoru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Cheng Wang
- Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Huiyao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
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15
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Dejenie TA, Abebe EC, Mengstie MA, Seid MA, Gebeyehu NA, Adella GA, Kassie GA, Gebrekidan AY, Gesese MM, Tegegne KD, Anley DT, Feleke SF, Zemene MA, Dessie AM, Moges N, Kebede YS, Bantie B, Adugna DG. Dyslipidemia and serum cystatin C levels as biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1124367. [PMID: 37082121 PMCID: PMC10112538 DOI: 10.3389/fendo.2023.1124367] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/22/2023] [Indexed: 04/08/2023] Open
Abstract
BackgroundDiabetic nephropathy is a leading cause of end-stage renal disease. The diagnostic markers of nephropathy, including the presence of albuminuria and/or a reduced estimated glomerular filtration rate, are not clinically ideal, and most of them are raised after a significant reduction in renal function. Therefore, it is crucial to seek more sensitive and non-invasive biomarkers for the diagnosis of diabetic nephropathy.Objective of the studyThis study aimed to investigate the serum cystatin C levels and dyslipidemia for the detection of diabetic nephropathy in patients with type 2 diabetes mellitus.MethodologyA hospital-based comparative cross-sectional study was conducted from December 2021 to August 2022 in Tikur, Anbessa specialized teaching hospital with a sample size of 140 patients with type2 diabetes mellitus. Socio-demographic data was collected using a structured questionnaire, and 5 mL of blood was collected from each participant following overnight fasting for biochemical analyses.ResultsIn type 2 diabetes patients with nephropathy, we found significant lipoprotein abnormalities and an increase in serum cystatin C (P < 0.001) compared to those without nephropathy. Serum cystatin C, systolic blood pressure, fasting blood glucose, total cholesterol, triglyceride, low density lipoprotein, very low-density lipoprotein, high density lipoprotein, and duration of diabetes were identified as being significantly associated with diabetic nephropathy (P < 0.05) in multivariable logistic regression analysis. The mean values of total cholesterol levels, triglyceride levels, and high-density lipoprotein cholesterol levels were also found to be significantly higher (P < 0.05) in females as compared to male type-2 diabetic patients. The fasting blood glucose levels and lipid profiles of the participants were found to be significantly associated with serum cystatin C levels.ConclusionThe present study found significant serum cystatin C and lipoprotein abnormalities in T2DM patients with diabetic nephropathy when compared with those without diabetic nephropathy, and these lipoprotein abnormalities were significantly associated with serum cystatin C levels.
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Affiliation(s)
- Tadesse Asmamaw Dejenie
- Department of Medical Biochemistry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- *Correspondence: Tadesse Asmamaw Dejenie,
| | - Endeshaw Chekol Abebe
- Department of Biochemistry, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Misganaw Asmamaw Mengstie
- Department of Biochemistry, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Mohammed Abdu Seid
- Department of Physiology, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Natnael Atnafu Gebeyehu
- Department of Midwifery, College of Medicine and Health Science, Wolaita Sodo University, Sodo, Ethiopia
| | - Getachew Asmare Adella
- Department of Reproductive Health and Nutrition, School of Public Health, Woliata Sodo University, Sodo, Ethiopia
| | - Gizchew Ambaw Kassie
- Department of Epidemiology and Biostatistics, School of Public Health, Woliata Sodo University, Sodo, Ethiopia
| | - Amanuel Yosef Gebrekidan
- Department of Public Health, School of Public Health, College of Health Sciences and Medicine, Wolaita Sodo University, Sodo, Ethiopia
| | - Molalegn Mesele Gesese
- Department of Midwifery, College of Medicine and Health Science, Wolaita Sodo University, Sodo, Ethiopia
| | - Kirubel Dagnaw Tegegne
- Department of Nursing, College of Medicine and Health Science, Wollo University, Dessie, Ethiopia
| | - Denekew Tenaw Anley
- Department of Public Health, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Sefineh Fenta Feleke
- Department of Public Health, College of Health Sciences, Woldia University, Woldia, Ethiopia
| | - Melkamu Aderajew Zemene
- Department of Public Health, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Anteneh Mengist Dessie
- Department of Public Health, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Natnael Moges
- Department of Pediatrics and Child Health Nursing, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Yenealem Solomon Kebede
- Department of Medical Laboratory Science, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Berihun Bantie
- Department of Comprehensive Nursing, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Dagnew Getnet Adugna
- Department of Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
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16
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Khurana I, Kaipananickal H, Maxwell S, Birkelund S, Syreeni A, Forsblom C, Okabe J, Ziemann M, Kaspi A, Rafehi H, Jørgensen A, Al-Hasani K, Thomas MC, Jiang G, Luk AO, Lee HM, Huang Y, Thewjitcharoen Y, Nakasatien S, Himathongkam T, Fogarty C, Njeim R, Eid A, Hansen TW, Tofte N, Ottesen EC, Ma RC, Chan JC, Cooper ME, Rossing P, Groop PH, El-Osta A. Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes. J Clin Invest 2023; 133:160959. [PMID: 36633903 PMCID: PMC9927943 DOI: 10.1172/jci160959] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.
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Affiliation(s)
- Ishant Khurana
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Harikrishnan Kaipananickal
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Scott Maxwell
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Sørine Birkelund
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark
| | - Anna Syreeni
- 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
| | - Carol Forsblom
- 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
| | - Jun Okabe
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Mark Ziemann
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Antony Kaspi
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Haloom Rafehi
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Anne Jørgensen
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Keith Al-Hasani
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Merlin C. Thomas
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | | | - Andrea O.Y. Luk
- Department of Medicine and Therapeutics,,Hong Kong Institute of Diabetes and Obesity,,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Heung Man Lee
- Department of Medicine and Therapeutics,,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | | | | | | | - Christopher Fogarty
- 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
| | - Rachel Njeim
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Assaad Eid
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Nete Tofte
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | | | - Ronald C.W. Ma
- Department of Medicine and Therapeutics,,Hong Kong Institute of Diabetes and Obesity,,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Juliana C.N. Chan
- Department of Medicine and Therapeutics,,Hong Kong Institute of Diabetes and Obesity,,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Mark E. Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Per-Henrik Groop
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,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
| | - Assam El-Osta
- Epigenetics in Human Health and Disease Laboratory and,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.,University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark.,Hong Kong Institute of Diabetes and Obesity,,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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17
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Saka SO, Salisu YY, Sahabi HM, Sanusi KO, Ibrahim KG, Abubakar MB, Isa SA, Liman MG, Shehu S, Malami I, Chan KW, Azmi NH, Imam MU. Nutrigenomic Effects of White Rice and Brown Rice on the Pathogenesis of Metabolic Disorders in a Fruit Fly Model. Molecules 2023; 28:532. [PMID: 36677591 PMCID: PMC9865196 DOI: 10.3390/molecules28020532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/24/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
Consumption of white rice (WR) has been shown to predispose individuals to metabolic disorders. However, brown rice (BR), which is relatively richer in bioactive compounds, possesses anti-glycaemic and antioxidant effects. In this study, fifteen cultivars of paddy rice that are predominantly consumed in North West Nigeria were analysed for their nutritional composition, bioactive contents and effects on metabolic outcomes in a fruit fly model. Gene expression analyses were conducted on the whole fly, targeting dPEPCK, dIRS, and dACC. The protein, carbohydrate, and fibre contents and bioactives of all BR cultivars were significantly different (p < 0.05) from the WR cultivars. Moreover, it was demonstrated that the glucose and trehalose levels were significantly higher (p < 0.05), while glycogen was significantly lower (p < 0.05) in the WR groups compared to the BR groups. Similarly, the expression of dACC and dPEPCK was upregulated, while that of dIRS was downregulated in the WR groups compared to the BR groups. Sex differences (p < 0.05) were observed in the WR groups in relation to the nutrigenomic effects. Our findings confirm metabolic perturbations in fruit flies following consumption of WR via distortion of insulin signalling and activation of glycogenolysis and gluconeogenesis. BR prevented these metabolic changes possibly due to its richer nutritional composition.
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Affiliation(s)
- Saheed Olanrewaju Saka
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Yusuf Yahaya Salisu
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Biochemistry and Molecular Biology, Faculty of Science, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Hauwa’u Muhammad Sahabi
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Biochemistry and Molecular Biology, Faculty of Science, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Kamaldeen Olalekan Sanusi
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Kasimu Ghandi Ibrahim
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Murtala Bello Abubakar
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Suleiman Ahmed Isa
- Department of Biochemistry and Molecular Biology, Faculty of Science, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Muhammad Gidado Liman
- Department of Pure and Applied Chemistry, Faculty of Science, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Sha’aya’u Shehu
- Department of Biochemistry and Molecular Biology, Faculty of Science, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Ibrahim Malami
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Pharmacognosy and Ethnopharmacy, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
| | - Kim Wei Chan
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM, Serdang 43400, Selangor, Malaysia
| | - Nur Hanisah Azmi
- Faculty of Food Science and Nutrition, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, Malaysia
| | - Mustapha Umar Imam
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2346, Nigeria
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18
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Ren G, Jiao P, Yan Y, Ma X, Qin G. Baicalin Exerts a Protective Effect in Diabetic Nephropathy by Repressing Inflammation and Oxidative Stress Through the SphK1/S1P/NF-κB Signaling Pathway. Diabetes Metab Syndr Obes 2023; 16:1193-1205. [PMID: 37131503 PMCID: PMC10149099 DOI: 10.2147/dmso.s407177] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/14/2023] [Indexed: 05/04/2023] Open
Abstract
Background Inflammation and oxidative stress contribute to the development of diabetic nephropathy (DN). Baicalin (BA) shows renal protection against DN through its anti-inflammatory and anti-oxidant properties. However, the molecular mechanism by which BA exerts the therapeutic effects on DN remains to be investigated. Methods The db/db mice and high glucose (HG)-induced HK-2 cells were used as the in vivo and in vitro model of DN, respectively. The effects of BA were assessed by detecting the related blood and urine biochemical parameters, kidney histopathology, inflammatory cytokine production, oxidative stress indicators, and apoptosis. Cell viability and apoptosis were detected by CCK-8 assay and TUNEL assay, respectively. Related protein levels were measured by an immunoblotting method. Results In db/db model mice, BA reduced serum glucose concentration, decreased blood lipid levels, ameliorated kidney functions, and decreased histopathological changes in kidney tissues. BA also alleviated oxidative stress and inflammation in db/db mice. In addition, BA blocked the activation of sphingosine kinases type 1/sphingosine 1-phosphate (SphK1/S1P)/NF-κB pathway in db/db mice. In HK-2 cells, BA hindered HG-induced apoptosis, oxidative stress and inflammation, while overexpression of SphK1 or S1P could reverse these effects. BA alleviated HG-induced apoptosis, oxidative stress and inflammation in HK-2 cells through the S1P/NF-κB pathway. Furthermore, BA blocked the NF-κB signaling by diminishing p65 nuclear translocation via the SphK1/S1P pathway. Conclusion Our study strongly suggests that BA protects against DN via ameliorating inflammation, oxidative stress and apoptosis through the SphK1/S1P/NF-κB pathway. This study provides a novel insight into the therapeutic effects of BA in DN.
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Affiliation(s)
- Gaofei Ren
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Pengfei Jiao
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Yushan Yan
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Xiaojun Ma
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
- Correspondence: Xiaojun Ma; Guijun Qin, Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People’s Republic of China, Tel +86-0371-66295052, Email ;
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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Drake AM, Coughlan MT, Christophersen CT, Snelson M. Resistant Starch as a Dietary Intervention to Limit the Progression of Diabetic Kidney Disease. Nutrients 2022; 14:4547. [PMID: 36364808 PMCID: PMC9656781 DOI: 10.3390/nu14214547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 08/15/2023] Open
Abstract
Diabetes is the leading cause of kidney disease, and as the number of individuals with diabetes increases there is a concomitant increase in the prevalence of diabetic kidney disease (DKD). Diabetes contributes to the development of DKD through a number of pathways, including inflammation, oxidative stress, and the gut-kidney axis, which may be amenable to dietary therapy. Resistant starch (RS) is a dietary fibre that alters the gut microbial consortium, leading to an increase in the microbial production of short chain fatty acids. Evidence from animal and human studies indicate that short chain fatty acids are able to attenuate inflammatory and oxidative stress pathways, which may mitigate the progression of DKD. In this review, we evaluate and summarise the evidence from both preclinical models of DKD and clinical trials that have utilised RS as a dietary therapy to limit the progression of DKD.
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Affiliation(s)
- Anna M. Drake
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
| | - Melinda T. Coughlan
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
- Baker Heart & Diabetes Institute, Melbourne 3004, Australia
| | - Claus T. Christophersen
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
- WA Human Microbiome Collaboration Centre, School of Molecular Life Sciences, Curtin University, Bentley 6102, Australia
| | - Matthew Snelson
- Glycation, Nutrition and Metabolism Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne 3004, Australia
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Wang M, Pang Y, Guo Y, Tian L, Liu Y, Shen C, Liu M, Meng Y, Cai Z, Wang Y, Zhao W. Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease. Front Pharmacol 2022; 13:970601. [PMID: 36120335 PMCID: PMC9479190 DOI: 10.3389/fphar.2022.970601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.
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21
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Huang YC, Hsu SM, Shie FS, Shiao YJ, Chao LJ, Chen HW, Yao HH, Chien MA, Lin CC, Tsay HJ. Reduced mitochondria membrane potential and lysosomal acidification are associated with decreased oligomeric Aβ degradation induced by hyperglycemia: A study of mixed glia cultures. PLoS One 2022; 17:e0260966. [PMID: 35073330 PMCID: PMC8786178 DOI: 10.1371/journal.pone.0260966] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/20/2021] [Indexed: 01/21/2023] Open
Abstract
Diabetes is a risk factor for Alzheimer’s disease (AD), a chronic neurodegenerative disease. We and others have shown prediabetes, including hyperglycemia and obesity induced by high fat and high sucrose diets, is associated with exacerbated amyloid beta (Aβ) accumulation and cognitive impairment in AD transgenic mice. However, whether hyperglycemia reduce glial clearance of oligomeric amyloid-β (oAβ), the most neurotoxic Aβ aggregate, remains unclear. Mixed glial cultures simulating the coexistence of astrocytes and microglia in the neural microenvironment were established to investigate glial clearance of oAβ under normoglycemia and chronic hyperglycemia. Ramified microglia and low IL-1β release were observed in mixed glia cultures. In contrast, amoeboid-like microglia and higher IL-1β release were observed in primary microglia cultures. APPswe/PS1dE9 transgenic mice are a commonly used AD mouse model. Microglia close to senile plaques in APPswe/PS1dE9 transgenic mice exposed to normoglycemia or chronic hyperglycemia exhibited an amoeboid-like morphology; other microglia were ramified. Therefore, mixed glia cultures reproduce the in vivo ramified microglial morphology. To investigate the impact of sustained high-glucose conditions on glial oAβ clearance, mixed glia were cultured in media containing 5.5 mM glucose (normal glucose, NG) or 25 mM glucose (high glucose, HG) for 16 days. Compared to NG, HG reduced the steady-state level of oAβ puncta internalized by microglia and astrocytes and decreased oAβ degradation kinetics. Furthermore, the lysosomal acidification and lysosomal hydrolysis activity of microglia and astrocytes were lower in HG with and without oAβ treatment than NG. Moreover, HG reduced mitochondrial membrane potential and ATP levels in mixed glia, which can lead to reduced lysosomal function. Overall, continuous high glucose reduces microglial and astrocytic ATP production and lysosome activity which may lead to decreased glial oAβ degradation. Our study reveals diabetes-induced hyperglycemia hinders glial oAβ clearance and contributes to oAβ accumulation in AD pathogenesis.
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Affiliation(s)
- Yung-Cheng Huang
- Department of Physical Medicine and Rehabilitation, Cheng-Hsin General Hospital, Taipei, Taiwan, Republic of China
- National Taipei University of Nursing and Health Sciences, Taipei City, Taiwan, R.O.C
| | - Shu-Meng Hsu
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Feng-Shiun Shie
- Center for Neuropsychiatric Research National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C
| | - Young-Ji Shiao
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan
- Ph.D. Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan, R.O.C
- Institute of Biopharmaceutical Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Li-Jung Chao
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Hui-Wen Chen
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Heng-Hsiang Yao
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Meng An Chien
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
| | - Chung-Chih Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- Biophotonics Interdisciplinary Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- * E-mail: (CCL); (HJT)
| | - Huey-Jen Tsay
- Institute of Neuroscience, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, R.O.C
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- * E-mail: (CCL); (HJT)
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22
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El Askary A, Gharib AF, Almehmadi M, Bakhuraysah MM, Al Hajjiahmed AA, Al-Hejji LI, Alharthi MS, Shafie A. The role of vitamin D deficiency and elevated inflammatory biomarkers as risk factors for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus. OPEN CHEM 2021. [DOI: 10.1515/chem-2021-0107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Albuminuria is the most sensitive marker for the early recognition of DN. Therefore, we aimed to study the risk factors of albuminuria as a marker of DN among diabetic patients. The study included 41 patients with type 2 diabetes mellitus (T2DM), 50 type 2 diabetic nephropathy (T2DN) patients with macroalbuminuria, 43 T2DN patients with microalbuminuria and 38 healthy controls. Logistic regression was used to detect the most significant risk factors for albuminuria. A high statistically significant difference was found between the groups regarding age, sex, body mass index (BMI), diabetes mellitus (DM) duration, glucose, glycated haemoglobin (HbA1c), creatinine, glomerular filtration rate (GFR), lipid profile, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), the albumin–creatinine ratio (ACR), vitamin D, total parathyroid hormone (PTH), urea, total calcium and chemerin (p < 0.001). It was found that the duration of DM, BMI, glucose, GFR, total cholesterol (TC), low-density lipoprotein (LDL), TNF-α, IL-6, CRP, ACR, vitamin D, PTH and chemerin are significant albuminuria risk factors in DN. Vitamin D deficiency and associated inflammatory mediators such as chemerin, TNF-α, IL-6 and CRP are the most essential risk factors for albuminuria in T2DM patients.
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Affiliation(s)
- Ahmad El Askary
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
| | - Amal F. Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
| | - Mazen Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
| | - Maha Mahfouz Bakhuraysah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
| | - Abdulaziz Ali Al Hajjiahmed
- Reference Laboratory, Laboratories and Blood Banks Administration in Al-Ahsa Health Cluster, Ministry of Health , Al-Ahsa , Saudi Arabia
| | - Layla Ibrahim Al-Hejji
- Curative Services for Primary Health Care in Al-Ahsa Health Cluster, Ministry of Health , Al-Ahsa , Saudi Arabia
| | - Mohammed S. Alharthi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
| | - Alaa Shafie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University , PO Box 11099 , Taif 21944 , Saudi Arabia
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23
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Wang H, Zhang S, Guo J. Lipotoxic Proximal Tubular Injury: A Primary Event in Diabetic Kidney Disease. Front Med (Lausanne) 2021; 8:751529. [PMID: 34760900 PMCID: PMC8573085 DOI: 10.3389/fmed.2021.751529] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/27/2021] [Indexed: 01/23/2023] Open
Abstract
The pathogenesis of diabetic nephropathy is a complex process that has a great relationship with lipotoxicity. Since the concept of “nephrotoxicity” was proposed, many studies have confirmed that lipotoxicity plays a significant role in the progression of diabetic nephropathy and causes various renal dysfunction. This review will make a brief summary of renal injury caused by lipotoxicity that occurs primarily and predominantly in renal tubules during diabetic progression, further leading to glomerular dysfunction. The latest research suggests that lipotoxicity-mediated tubular injury may be a major event in diabetic nephropathy.
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Affiliation(s)
- Hua Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Nephrology, Nephropathy Research Institutes of Zhengzhou University, Zhengzhou, China
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24
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Gong L, Wang C, Ning G, Wang W, Chen G, Wan Q, Qin G, Yan L, Wang G, Qin Y, Luo Z, Tang X, Huo Y, Hu R, Ye Z, Shi L, Gao Z, Su Q, Mu Y, Zhao J, Chen L, Zeng T, Yu X, Li Q, Shen F, Zhang Y, Wang Y, Deng H, Liu C, Wu S, Yang T, Bi Y, Lu J, Li M, Xu Y, Xu M, Wang T, Zhao Z, Hou X, Chen L. High concentrations of triglycerides are associated with diabetic kidney disease in new-onset type 2 diabetes in China: Findings from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Diabetes Obes Metab 2021; 23:2551-2560. [PMID: 34322974 PMCID: PMC9291490 DOI: 10.1111/dom.14502] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/02/2021] [Accepted: 07/25/2021] [Indexed: 11/30/2022]
Abstract
AIMS The aims of this study were to evaluate the associations of metabolic abnormalities with incident diabetic kidney disease (DKD) and to explore whether dyslipidaemia, particularly high fasting triglyceride (TG), was associated with the development of DKD. METHODS In total, 11 142 patients with new-onset type 2 diabetes with baseline estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73 m2 were followed up during 2011-2016. Incident DKD was defined as eGFR <60 mL/min/1.73 m2 at follow-up. Multiple logistic regression analysis was conducted to explore the relationship of metabolic abnormalities at baseline and at follow-up with risks of DKD. High TG was defined by TG ≥1.70 mmol/L. Low high-density lipoprotein cholesterol (HDL-c) was defined by HDL-c <1.0 mmol/L for men or <1.3 mmol/L for women. RESULTS Participants who developed DKD had higher levels of waist circumference and systolic blood pressure, and lower levels of HDL-c at both baseline and follow-up visits. The DKD group also had higher levels of post-load plasma glucose and TG at follow-up. Multivariate logistic regression analysis revealed that both high TG at baseline [odds ratio (OR) = 1.37, p = .012) and high TG at follow-up (OR = 1.71, p < .001) were significantly associated with increased risks of DKD. Patients with high TG levels at both baseline and follow-up had higher risk of DKD compared with constantly normal TG (OR = 1.65, p < .001) after adjustment for covariates. CONCLUSIONS In a large population of patients with new-onset type 2 diabetes, a high TG level was an independent risk factor for the development of DKD. Tight TG control might delay the occurrence of DKD.
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Affiliation(s)
- Lei Gong
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
- Institute of Endocrine and Metabolic Diseases of Shandong UniversityJinanChina
- Key Laboratory of Endocrine and Metabolic DiseasesShandong Province Medicine & HealthJinanChina
- Jinan Clinical Research Center for Endocrine and Metabolic DiseasesJinanChina
| | - Chuan Wang
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
- Institute of Endocrine and Metabolic Diseases of Shandong UniversityJinanChina
- Key Laboratory of Endocrine and Metabolic DiseasesShandong Province Medicine & HealthJinanChina
- Jinan Clinical Research Center for Endocrine and Metabolic DiseasesJinanChina
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Gang Chen
- Fujian Provincial HospitalFujian Medical UniversityFuzhouChina
| | - Qin Wan
- The Affiliated Hospital of Luzhou Medical CollegeLuzhouChina
| | - Guijun Qin
- The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Li Yan
- Sun Yat‐sen Memorial HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Guixia Wang
- The First Hospital of Jilin UniversityChangchunChina
| | - Yingfen Qin
- The First Affiliated Hospital of Guangxi Medical UniversityNanningChina
| | - Zuojie Luo
- The First Affiliated Hospital of Guangxi Medical UniversityNanningChina
| | - Xulei Tang
- The First Hospital of Lanzhou UniversityLanzhouChina
| | - Yanan Huo
- Jiangxi Provincial People's Hospital Affiliated to Nanchang UniversityNanchangChina
| | - Ruying Hu
- Zhejiang Provincial Center for Disease Control and PreventionHangzhouChina
| | - Zhen Ye
- Zhejiang Provincial Center for Disease Control and PreventionHangzhouChina
| | - Lixin Shi
- Affiliated Hospital of Guiyang Medical CollegeGuiyangChina
| | | | - Qing Su
- Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Yiming Mu
- Chinese People's Liberation Army General HospitalBeijingChina
| | - Jiajun Zhao
- Shandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
| | - Lulu Chen
- Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Tianshu Zeng
- Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xuefeng Yu
- Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qiang Li
- The Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Feixia Shen
- The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Yinfei Zhang
- Central Hospital of Shanghai Jiading DistrictShanghaiChina
| | - Youmin Wang
- The First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Huacong Deng
- The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Chao Liu
- Jiangsu Province Hospital on Integration of Chinese and Western MedicineNanjingChina
| | - Shengli Wu
- Karamay Municipal People's HospitalXinjiangChina
| | - Tao Yang
- The First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jieli Lu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Mian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yu Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Min Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Tiange Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhiyun Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xinguo Hou
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
- Institute of Endocrine and Metabolic Diseases of Shandong UniversityJinanChina
- Key Laboratory of Endocrine and Metabolic DiseasesShandong Province Medicine & HealthJinanChina
- Jinan Clinical Research Center for Endocrine and Metabolic DiseasesJinanChina
| | - Li Chen
- Department of EndocrinologyQilu Hospital of Shandong UniversityJinanChina
- Institute of Endocrine and Metabolic Diseases of Shandong UniversityJinanChina
- Key Laboratory of Endocrine and Metabolic DiseasesShandong Province Medicine & HealthJinanChina
- Jinan Clinical Research Center for Endocrine and Metabolic DiseasesJinanChina
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25
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Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis. Int J Mol Sci 2021; 22:ijms222111857. [PMID: 34769288 PMCID: PMC8584225 DOI: 10.3390/ijms222111857] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/08/2021] [Accepted: 10/30/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.
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Abdelsattar S, Kasemy ZA, Elsayed M, Elrahem TA, Zewain SK. Targeted metabolomics as a tool for the diagnosis of kidney disease in Type II diabetes mellitus. Br J Biomed Sci 2021; 78:184-190. [PMID: 33656967 DOI: 10.1080/09674845.2021.1894705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background: Diabetic kidney disease (DKD) is an increasing health problem and an extra burden to health services. The study of characteristic metabolic alterations of DKD is crucial for a better understanding of pathogenesis to identify new potential biomarkers and drug targets. We hypothesized that metabolic profiling of amino acids, acylcarnitines, and organic acids are useful new biomarkers for the diagnosis of the early stages of DKDMethods: The hypothesis was testing in a case-control study of 232 patients with type 2 diabetes mellitus and 150 healthy controls. Patients were classified according to urinary albumin and estimated glomerular filtration rate (eGFR) into 100 with normoalbuminuria and 132 with microalbuminuria group. Eighteen AcylCNs and 17 amino acids were measured in the blood by tandem mass spectrometry while 17 urinary organic acids were quantitatively measured by gas chromatography - mass spectrometry.Results: Regression analysis found that dodecanoylcarnitines C12 (effect size 2.03 [95%CI 1.73-2.32]), triglylcarnitine C5:1 (2.01 [1.70-2.30]), and isovalerylcarnitine C5 (1.78 [1.48-2.07]) were stronger predictors of albumin/creatinine ratio than HbA1c (1.50 [1.20-1.78]) and hence they could serve as potential biomarkers for the diagnosis of the early stages of DKD.Conclusions: Targeted metabolic profiling offers a new, non-invasive approach for detecting biomarkers for the early diagnosis of DKD suggesting new pathogenetic phases that might be new targets for treatment.
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Affiliation(s)
- S Abdelsattar
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menoufia University, Shibin El Kom, Egypt
| | - Z A Kasemy
- Menoufia Faculty of Medicine, Public Health and Community Medicine, Shibin El Kom, Egypt
| | - M Elsayed
- Internal Medicine Department, Menoufia Faculty of Medicine, Shibin El Kom, Egypt
| | - T A Elrahem
- Resident of Internal Medicine, EL Menia General Hospital, EL Menia, Egypt
| | - S K Zewain
- Internal Medicine Department, Menoufia Faculty of Medicine, Shibin El Kom, Egypt
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Şahin İO. How curcumin affects hyperglycemia-induced optic nerve damage: A short review. J Chem Neuroanat 2021; 113:101932. [PMID: 33581265 DOI: 10.1016/j.jchemneu.2021.101932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 11/19/2022]
Abstract
Considered to be one of the most important non-contagious systemic diseases worldwide, diabetes mellitus is still a topical issue on the health agenda with the problems it causes. Exposure to long-term hyperglycemia causes diabetic complications (diabetic neuropathy, nephropathy and retinopathy). The optic nerve can suffer damage by both diabetic retinopathy and neuropathy during diabetes, both because it is formed by axons of retinal ganglion cells and these axons belong to the central nervous system. The issue of hyperglycemia on the optic nerve have been described as diabetic papillopathy, posterior ischemic optic neuropathy, nonarteritic anterior ischemic optic neuropathy and optic atrophy in clinical studies. Experimental studies indicated axon-myelin degeneration in addition to microvascular and ultrastructural changes caused by the hyperglycemia-induced optic nerve damage. Although there are several proposed biochemical mechanisms to cause these damages, oxidative stress emerges as an important factor among them. Oxidative stress leads to pathological state on the nerve cells by affecting the DNA, protein and lipids at different levels. These are causing deterioration on nerve conduction velocity, myelin sheath and nerve structure, neurotrophic support system, glial cells and nerve function. Curcumin, as an important antioxidant, can be an ideal prophylactic agent to eliminate damages on optic nerve. Curcumin helps to regulate the balance of antioxidant and reactive oxygen species by targeting various molecules (NF-κB, STAT3, MAPK, Mfn2, Nrf2, pro-inflammatory cytokines). In addition, it shows healing or preventive effects on myelin sheath damage via regulating ferritin protein in oligodendrocytes. It is also effective in preventing neurovascular damage.
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Affiliation(s)
- İzem Olcay Şahin
- Department of Histology and Embryology, Medical School, Ondokuz Mayis University, 55139 Samsun, Turkey.
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Chen LY, Huang CN, Liao CK, Chang HM, Kuan YH, Tseng TJ, Yen KJ, Yang KL, Lin HC. Effects of Rutin on Wound Healing in Hyperglycemic Rats. Antioxidants (Basel) 2020; 9:antiox9111122. [PMID: 33202817 PMCID: PMC7696622 DOI: 10.3390/antiox9111122] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/05/2020] [Accepted: 11/10/2020] [Indexed: 12/17/2022] Open
Abstract
Long-term poor glycemic control negatively affects macrovascular and microvascular diseases, as well as wound restoration. Buckwheat is a good source of rutin (quercetin-3-O-rutoside) and has benefits in regulating blood sugar. This study was to evaluate the antioxidant and anti-inflammatory effects of rutin on wound healing in streptozotocin-induced hyperglycemic rats. Eighteen male Wistar rats were randomly divided into three groups: normal (NDM), hyperglycemic (DM), and hyperglycemic with rutin (DMR). After induction of hyperglycemia for 2 days, a 15 × 15 mm wound was induced on the back of each rat. Intraperitoneal injection of rutin significantly ameliorated diabetes-induced body weight loss and improved metabolic dysfunctions of hyperglycemic rats. Based on appearance and histopathological staining, rutin promotes wound healing and inhibits production of inflammatory cells. The immunoblotting data indicated that rutin promotes production of antioxidant enzymes induced by nuclear factor erythroid 2-related factor 2 (NRF2), inhibits the expression of matrix metalloproteinases (MMPs) regulated by NF-κB, and decreases the expression of vascular endothelial growth factor (VEGF). It also promotes the expression of neurogenic-related protein (UCH-L1). The aforementioned results indicated that rutin reduces oxidative stress and inflammatory response in hyperglycemic rats, promoting wound healing and subsequently reducing the risk of wound ulcers.
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Affiliation(s)
- Li-You Chen
- Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan; (L.-Y.C.); (C.-K.L.); (T.-J.T.); (K.-J.Y.); (K.-L.Y.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - Chien-Ning Huang
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan;
- Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan
| | - Chih-Kai Liao
- Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan; (L.-Y.C.); (C.-K.L.); (T.-J.T.); (K.-J.Y.); (K.-L.Y.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - Hung-Ming Chang
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 40201, Taiwan;
| | - Yu-Hsiang Kuan
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan;
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - To-Jung Tseng
- Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan; (L.-Y.C.); (C.-K.L.); (T.-J.T.); (K.-J.Y.); (K.-L.Y.)
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
| | - Kai-Jung Yen
- Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan; (L.-Y.C.); (C.-K.L.); (T.-J.T.); (K.-J.Y.); (K.-L.Y.)
| | - Kai-Lin Yang
- Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan; (L.-Y.C.); (C.-K.L.); (T.-J.T.); (K.-J.Y.); (K.-L.Y.)
| | - Hsing-Chun Lin
- Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan
- Department of Nutrition, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan
- Correspondence: ; Tel.: +886-4-24739595-34301
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Lee H, Lee H, Lim Y. Vitamin D 3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice. Nutr Res 2020; 80:55-65. [PMID: 32693268 DOI: 10.1016/j.nutres.2020.06.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 05/20/2020] [Accepted: 06/04/2020] [Indexed: 12/16/2022]
Abstract
Oxidative stress and abnormal lipid metabolism in diabetes can trigger renal lipotoxicity, extending to diabetic nephropathy. Vitamin D3 has been known to be involved in lipid metabolism as well as insulin secretion or inflammation. Therefore, we hypothesized that vitamin D3 supplementation attenuated hyperglycemia-induced renal damage in diabetic mice. Diabetes was induced by a 40% kJ high-fat diet with 30 mg/kg body weight of streptozotocin by intraperitoneal injection twice in male C57BL/6J mice. Among diabetic mice (fasting blood glucose > 140 mg/dL), mice were supplemented with 300 ng/kg body weight of vitamin D3 dissolved in olive oil for 12 weeks. Normal control and diabetic control mice were orally administrated with olive oil as a vehicle. Normal control mice were fed with an AIN-93G diet during the experiment. Vitamin D3 supplementation in diabetic mice improved glucose intolerance and kidney function, demonstrated by diminishing glomerular areas. Vitamin D3 supplementation in diabetic mice significantly reduced triglycerides and low-density lipoprotein cholesterol in plasma as well as triglycerides and total cholesterol in the kidney. Furthermore, vitamin D3 supplementation attenuated lipid synthesis, oxidative stress, and apoptosis, accompanied by activation of β-oxidation, antioxidant defense enzymes, and autophagy in diabetic mice. In conclusion, vitamin D3 supplementation ameliorates hyperglycemia-induced renal damage through the regulation of lipid metabolisms, oxidative stress, apoptosis, and autophagy in diabetes. Vitamin D3 could be a promising nutrient to weaken diabetic nephropathy.
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Affiliation(s)
- Heeseung Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Korea.
| | - Heaji Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Korea.
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Korea.
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Jiang W, Wang J, Shen X, Lu W, Wang Y, Li W, Gao Z, Xu J, Li X, Liu R, Zheng M, Chang B, Li J, Yang J, Chang B. Establishment and Validation of a Risk Prediction Model for Early Diabetic Kidney Disease Based on a Systematic Review and Meta-Analysis of 20 Cohorts. Diabetes Care 2020; 43:925-933. [PMID: 32198286 DOI: 10.2337/dc19-1897] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/27/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND Identifying patients at high risk of diabetic kidney disease (DKD) helps improve clinical outcome. PURPOSE To establish a model for predicting DKD. DATA SOURCES The derivation cohort was from a meta-analysis. The validation cohort was from a Chinese cohort. STUDY SELECTION Cohort studies that reported risk factors of DKD with their corresponding risk ratios (RRs) in patients with type 2 diabetes were selected. All patients had estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) <30 mg/g at baseline. DATA EXTRACTION Risk factors and their corresponding RRs were extracted. Only risk factors with statistical significance were included in our DKD risk prediction model. DATA SYNTHESIS Twenty cohorts including 41,271 patients with type 2 diabetes were included in our meta-analysis. Age, BMI, smoking, diabetic retinopathy, hemoglobin A1c, systolic blood pressure, HDL cholesterol, triglycerides, UACR, and eGFR were statistically significant. All these risk factors were included in the model except eGFR because of the significant heterogeneity among studies. All risk factors were scored according to their weightings, and the highest score was 37.0. The model was validated in an external cohort with a median follow-up of 2.9 years. A cutoff value of 16 was selected with a sensitivity of 0.847 and a specificity of 0.677. LIMITATIONS There was huge heterogeneity among studies involving eGFR. More evidence is needed to power it as a risk factor of DKD. CONCLUSIONS The DKD risk prediction model consisting of nine risk factors established in this study is a simple tool for detecting patients at high risk of DKD.
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Affiliation(s)
- Wenhui Jiang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaofang Shen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Wenli Lu
- Department of Epidemiology and Health Statistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Yuan Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Wen Li
- Department of Epidemiology and Health Statistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhongai Gao
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jie Xu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaochen Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Ran Liu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Miaoyan Zheng
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Bai Chang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jing Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
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Sui G, Zhang B, Fei D, Wang H, Guo F, Luo Q. The lncRNA SNHG3 accelerates papillary thyroid carcinoma progression via the miR-214-3p/PSMD10 axis. J Cell Physiol 2020; 235:6615-6624. [PMID: 32048306 DOI: 10.1002/jcp.29557] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 01/08/2020] [Indexed: 12/15/2022]
Abstract
Small nucleolar RNA host gene 3 (SNHG3) is a long noncoding RNA (lncRNA), which is known to promote oncogenesis in many cancers but its role in human papillary thyroid carcinoma (PTC) remains poorly understood. We therefore assessed SNHG3 expression in PTC tissues via quantitative reverse transcription polymerase chain reaction. We additionally knocked down SNHG3 in PTC cells using short-hairpin RNAs (shRNAs) to explore its functional roles in PTC. The ability of SNHG3 to bind to specific microRNAs (miRNAs) was predicted using a bioinformatics tool, and this binding was confirmed via dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. We then used a tumor xenograft model to assess the relevance of SNHG3 in vivo. We determined SNHG3 expression to be elevated in PTC tissues relative to controls, with advanced tumor-node-metastasis stage and lymph node metastasis being associated with this expression. Knocking down SNHG3 significantly reduced in vitro PTC cell migration, invasion, proliferation, and colony formation, and it further slowed the growth of tumors in vivo. We found that SNHG3 could bind to miR-214-3p as a competing endogenous RNA (ceRNA) for this miRNA, thereby regulating proteasome 26S subunit non-ATPase 10 (PSMD10) expression, a miR-214-3p target. These results thus indicate that SNHG3 is an oncogenic lncRNA in PTC, acting at least in part via the miR-214-3p/PSMD10 axis.
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Affiliation(s)
- Guoqing Sui
- Department of Ultrasonographic, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Butian Zhang
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Dan Fei
- Department of Ultrasonographic, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Hui Wang
- Department of Ultrasonographic, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Feng Guo
- Department of Ultrasonographic, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qiang Luo
- Department of Ultrasonographic, China-Japan Union Hospital of Jilin University, Changchun, China
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Bernardo-Bermejo S, Sánchez-López E, Castro-Puyana M, Benito-Martínez S, Lucio-Cazaña FJ, Marina ML. A Non-Targeted Capillary Electrophoresis-Mass Spectrometry Strategy to Study Metabolic Differences in an In vitro Model of High-Glucose Induced Changes in Human Proximal Tubular HK-2 Cells. Molecules 2020; 25:molecules25030512. [PMID: 31991659 PMCID: PMC7037647 DOI: 10.3390/molecules25030512] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy is characterized by the chronic loss of kidney function due to high glucose renal levels. HK-2 proximal tubular cells are good candidates to study this disease. The aim of this work was to study an in vitro model of high glucose-induced metabolic alterations in HK-2 cells to contribute to the pathogenesis of this diabetic complication. An untargeted metabolomics strategy based on CE-MS was developed to find metabolites affected under high glucose conditions. Intracellular and extracellular fluids from HK-2 cells treated with 25 mM glucose (high glucose group), with 5.5 mM glucose (normal glucose group), and with 5.5 mM glucose and 19.5 mM mannitol (osmotic control group) were analyzed. The main changes induced by high glucose were found in the extracellular medium where increased levels of four amino acids were detected. Three of them (alanine, proline, and glutamic acid) were exported from HK-2 cells to the extracellular medium. Other affected metabolites include Amadori products and cysteine, which are more likely cause and consequence, respectively, of the oxidative stress induced by high glucose in HK-2 cells. The developed CE-MS platform provides valuable insight into high glucose-induced metabolic alterations in proximal tubular cells and allows identifying discriminative molecules of diabetic nephropathy.
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Affiliation(s)
- Samuel Bernardo-Bermejo
- Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-B.); (E.S.-L.); (M.C.-P.)
| | - Elena Sánchez-López
- Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-B.); (E.S.-L.); (M.C.-P.)
- Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain
| | - María Castro-Puyana
- Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-B.); (E.S.-L.); (M.C.-P.)
- Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain
| | - Selma Benito-Martínez
- Departamento de Biología de Sistemas, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-M.); (F.J.L.-C.)
- “Ramón y Cajal” Health Research Institute (IRYCIS), Universidad de Alcalá, 28871 Madrid, Spain
| | - Francisco Javier Lucio-Cazaña
- Departamento de Biología de Sistemas, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-M.); (F.J.L.-C.)
| | - María Luisa Marina
- Departamento de Química Analítica, Química Física e Ingeniería Química, Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain; (S.B.-B.); (E.S.-L.); (M.C.-P.)
- Instituto de Investigación Química Andrés M. del Río (IQAR), Universidad de Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871 Madrid, Spain
- Correspondence: ; Tel.: +34-91-885-4935; Fax: +34-91-885-4971
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Zhou T, Sun L, Yang S, Lv Y, Cao Y, Gang X, Wang G. 20(S)-Ginsenoside Rg3 Protects Kidney from Diabetic Kidney Disease via Renal Inflammation Depression in Diabetic Rats. J Diabetes Res 2020; 2020:7152176. [PMID: 32258169 PMCID: PMC7106937 DOI: 10.1155/2020/7152176] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/26/2020] [Accepted: 02/15/2020] [Indexed: 02/04/2023] Open
Abstract
20(S)-Ginsenoside Rg3 (20(S)-Rg3) has been shown to induce apoptosis by interfering with several signaling pathways. Furthermore, it has been reported to have anticancer and antidiabetic effects. In order to detect the protective effect of 20(S)-Rg3 on diabetic kidney disease (DKD), diabetic rat models which were established by administering high-sugar, high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), and age-matched wild-type (WT) rat were given 20(S)-Rg3 for 12 weeks, with three groups: control group (normal adult rats with saline), diabetic group (diabetic rats with saline), and 20(S)-Rg3 treatment group (diabetic rats with 20(S)-Rg3 (10 mg/kg body weight/day)). The biochemical indicators and the changes in glomerular basement membrane and mesangial matrix were detected. TUNEL staining was used to detect glomerular and renal tubular cell apoptosis. Immunohistochemical staining was used to detect the expression of fibrosis factors and inflammation factors in rat kidney tissues. Through periodic acid-Schiff staining, we observed that the change in renal histology was improved and renal tubular epithelial cell apoptosis decreased significantly by treatment with 20(S)-Rg3. Plus, the urine protein decreased in the rats with the 20(S)-Rg3 treatment. Fasting blood glucose, creatinine, total cholesterol, and triglyceride levels in the 20(S)-Rg3 treatment group were all lower than those in the diabetic group. Mechanistically, 20(S)-Rg3 dramatically downregulated the expression of TGF-β1, NF-κB65, and TNF-α in the kidney. These resulted in a significant prevention of renal damage from the inflammation. The results of the current study suggest that 20(S)-Rg3 could potentially be used as a novel treatment against DKD.
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Affiliation(s)
- Tong Zhou
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - Lin Sun
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - Shuo Yang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - You Lv
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - Yue Cao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, 130061 Changchun, Jilin Province, China
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Abstract
PURPOSE OF REVIEW The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. RECENT FINDINGS Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.
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Affiliation(s)
- G Michelle Ducasa
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, 1580 NW 10th Avenue, Miami, FL, USA.
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
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