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Yeh TH, Tu KC, Wang HY, Chen JY. From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease. Int J Mol Sci 2024; 25:1755. [PMID: 38339031 PMCID: PMC10855633 DOI: 10.3390/ijms25031755] [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: 01/05/2024] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical applications. This review also highlights the links between renal injury and the pathophysiological mechanisms underlying AKI and AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and the cellular senescence of renal cells. Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis. The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact.
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Affiliation(s)
- Tzu-Hsuan Yeh
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan; (T.-H.Y.); (H.-Y.W.)
| | - Kuan-Chieh Tu
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan;
| | - Hsien-Yi Wang
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan; (T.-H.Y.); (H.-Y.W.)
- Department of Sport Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
| | - Jui-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan; (T.-H.Y.); (H.-Y.W.)
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan
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Shi C, Wan Y, He A, Wu X, Shen X, Zhu X, Yang J, Zhou Y. Urinary metabolites associate with the presence of diabetic kidney disease in type 2 diabetes and mediate the effect of inflammation on kidney complication. Acta Diabetol 2023; 60:1199-1207. [PMID: 37184672 PMCID: PMC10359369 DOI: 10.1007/s00592-023-02094-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/10/2023] [Indexed: 05/16/2023]
Abstract
AIMS Diabetic kidney disease (DKD) is the one of the leading causes of end-stage kidney disease. Unraveling novel biomarker signatures capable to identify patients with DKD is favorable for tackle the burden. Here, we investigated the possible association between urinary metabolites and the presence of DKD in type 2 diabetes (T2D), and further, whether the associated metabolites improve discrimination of DKD and mediate the effect of inflammation on kidney involvement was evaluated. METHODS Two independent cohorts comprising 192 individuals (92 DKD) were analyzed. Urinary metabolites were analyzed by targeted metabolome profiling and inflammatory cytokine IL-18 were measured by ELISA. Differentially expressed metabolites were selected and mediation analysis was carried out. RESULTS Seven potential metabolite biomarkers (i.e., S-Adenosyl-L-homocysteine, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid) were identified using the discovery and validation design. In the pooled analysis, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were markedly and independently associated with DKD. The composite index of 7 potential metabolite biomarkers (CMI) mediated 32.99% of the significant association between the inflammatory IL-18 and DKD. Adding the metabolite biomarkers improved the discrimination of DKD. CONCLUSIONS In T2D, several associated urinary metabolites were identified to improve the prediction of DKD. Whether interventions aimed at reducing CMI also reduce the risk of DKD especially in patients with high IL-18 needs further investigations.
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Affiliation(s)
- Caifeng Shi
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Yemeng Wan
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Aiqin He
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Xiaomei Wu
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Xinjia Shen
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Xueting Zhu
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China
| | - Junwei Yang
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China.
| | - Yang Zhou
- Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, No. 262 N Zhongshan Road, Nanjing, 210003, Jiangsu, China.
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Petrica L, Vlad A, Gadalean F, Muntean DM, Vlad D, Dumitrascu V, Bob F, Milas O, Suteanu-Simulescu A, Glavan M, Jianu DC, Ursoniu S, Balint L, Mogos-Stefan M, Ienciu S, Cretu OM, Popescu R. Mitochondrial DNA Changes in Blood and Urine Display a Specific Signature in Relation to Inflammation in Normoalbuminuric Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients. Int J Mol Sci 2023; 24:9803. [PMID: 37372951 DOI: 10.3390/ijms24129803] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/05/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Mitochondrial dysfunction is an important mechanism contributing to the development and progression of diabetic kidney disease (DKD). Mitochondrial DNA (mtDNA) levels in blood and urine were evaluated in relation to podocyte injury and proximal tubule (PT) dysfunction, as well as to a specific inflammatory response in normoalbuminuric DKD. A total of 150 type 2 diabetes mellitus (DM) patients (52 normoalbuminuric, 48 microalbuminuric, and 50 macroalbuminuric ones, respectively) and 30 healthy controls were assessed concerning the urinary albumin/creatinine ratio (UACR), biomarkers of podocyte damage (synaptopodin and podocalyxin), PT dysfunction (kidney injury molecule-1 (KIM-1) and N-acetyl-β-(D)-glucosaminidase (NAG)), and inflammation (serum and urinary interleukins (IL-17A, IL-18, and IL-10)). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine via qRT-PCR. MtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies via analysis of the CYTB/B2M and ND2/B2M ratio. Multivariable regression analysis provided models in which serum mtDNA directly correlated with IL-10 and indirectly correlated with UACR, IL-17A, and KIM-1 (R2 = 0.626; p < 0.0001). Urinary mtDNA directly correlated with UACR, podocalyxin, IL-18, and NAG, and negatively correlated with eGFR and IL-10 (R2 = 0.631; p < 0.0001). Mitochondrial DNA changes in serum and urine display a specific signature in relation to inflammation both at the podocyte and tubular levels in normoalbuminuric type 2 DM patients.
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Affiliation(s)
- Ligia Petrica
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Center for Translational Research and Systems Medicine, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Adrian Vlad
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Internal Medicine II, Division of Diabetes and Metabolic Diseases, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Florica Gadalean
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Danina Mirela Muntean
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Center for Translational Research and Systems Medicine, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Department of Functional Sciences III, Division of Pathophysiology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Daliborca Vlad
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Biochemistry and Pharmacology IV, Division of Pharmacology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Victor Dumitrascu
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Biochemistry and Pharmacology IV, Division of Pharmacology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Flaviu Bob
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Oana Milas
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Anca Suteanu-Simulescu
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Mihaela Glavan
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Dragos Catalin Jianu
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Neurosciences VIII, Division of Neurology I, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Sorin Ursoniu
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Center for Translational Research and Systems Medicine, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Functional Sciences III, Division of Public Health and Health and History of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Lavinia Balint
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Maria Mogos-Stefan
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Silvia Ienciu
- Department of Internal Medicine II, Division of Nephrology, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
| | - Octavian Marius Cretu
- Department of Surgery I, Division of Surgical Semiology I, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- Emergency Clinical Municipal Hospital Timisoara, 300041 Timisoara, Romania
| | - Roxana Popescu
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
- County Emergency Hospital Timisoara, 300723 Timisoara, Romania
- Department of Microscopic Morphology II, Division of Cell and Molecular Biology II, "Victor Babes" University of Medicine and Pharmacy, No. 2, Eftimie Murgu Sq., 300041 Timisoara, Romania
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Barrios-Nolasco A, Domínguez-López A, Miliar-García A, Cornejo-Garrido J, Jaramillo-Flores ME. Anti-Inflammatory Effect of Ethanolic Extract from Tabebuia rosea (Bertol.) DC., Quercetin, and Anti-Obesity Drugs in Adipose Tissue in Wistar Rats with Diet-Induced Obesity. Molecules 2023; 28:molecules28093801. [PMID: 37175211 PMCID: PMC10180162 DOI: 10.3390/molecules28093801] [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: 03/17/2023] [Revised: 04/18/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is characterized by the excessive accumulation of fat, which triggers a low-grade chronic inflammatory process. Currently, the search for compounds with anti-obesogenic effects that help reduce body weight, as well as associated comorbidities, continues. Among this group of compounds are plant extracts and flavonoids with a great diversity of action mechanisms associated with their beneficial effects, such as anti-inflammatory effects and/or as signaling molecules. In the bark of Tabebuia rosea tree, there are different classes of metabolites with anti-inflammatory properties, such as quercetin. Therefore, the present work studied the effect of the ethanolic extract of T. rosea and quercetin on the mRNA of inflammation markers in obesity compared to the drugs currently used. Total RNA was extracted from epididymal adipose tissue of high-fat diet-induced obese Wistar rats treated with orlistat, phentermine, T. rosea extract, and quercetin. The rats treated with T. rosea and quercetin showed 36 and 31% reductions in body weight compared to the obese control, and they likewise inhibited pro-inflammatory molecules: Il6, Il1b, Il18, Lep, Hif1a, and Nfkb1 without modifying the expression of Socs1 and Socs3. Additionally, only T. rosea overexpressed Lipe. Both T. rosea and quercetin led to a reduction in the expression of pro-inflammatory genes, modifying signaling pathways, which led to the regulation of the obesity-inflammation state.
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Affiliation(s)
- Alejandro Barrios-Nolasco
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - Aarón Domínguez-López
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Angel Miliar-García
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Jorge Cornejo-Garrido
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - María Eugenia Jaramillo-Flores
- Laboratorio de Polímeros, Department de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional, Wilfrido Massieu s/n esq. Manuel I. Stampa. Col. Unidad Profesional Adolfo López Mateos, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07738, Mexico
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Proficient Novel Biomarkers Guide Early Detection of Acute Kidney Injury: A Review. Diseases 2022; 11:diseases11010008. [PMID: 36648873 PMCID: PMC9844481 DOI: 10.3390/diseases11010008] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/12/2022] [Accepted: 11/30/2022] [Indexed: 01/03/2023] Open
Abstract
The definition of acute kidney injury (AKI), despite improvements in criteria, continues to be based on the level of serum creatinine and urinary output that do not specifically indicate tubular function or injury, or glomerular function or injury that is not significant enough to warrant acute hospitalization of the patient. Finding novel biomarkers of AKI has become a major focus nowadays in nephrology to overcome the further complications of end stage renal disease (ESRD). Many compounds, such as KIM 1, IL 18, NGAL, uromodulin, calprotectin, vanin 1, galactin 3, platelet-derived growth factor (PDGF), urinary Na+/H+ exchanger isoform 3 (NHE3), retinol binding protein (RBP) and Cystatin C, are released from the renal tubules and thus any alterations in tubular function can be detected by measuring these parameters in urine. Additionally, glomerular injury can be detected by measuring immunoglobulin G, nephrin, podocalyxin, podocin, transferrin, netrin-1, pyruvate kinase M2, etc. in urine. These novel biomarkers will be useful for timing the initial insult and assessing the duration of AKI. According to available research, these biomarkers could be applied to assess the onset of AKI, distinguishing between kidney injury and dysfunction, directing the management of AKI, and enhancing disease diagnosis. Therefore, we intend to present recent developments in our understanding of significant biomarkers implicated in various aspects of renal damage. Numerous biomarkers are implicated in various pathophysiological processes that follow renal injury, and can improve prognosis and risk classification.
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Zheng X, Higdon L, Gaudet A, Shah M, Balistieri A, Li C, Nadai P, Palaniappan L, Yang X, Santo B, Ginley B, Wang XX, Myakala K, Nallagatla P, Levi M, Sarder P, Rosenberg A, Maltzman JS, de Freitas Caires N, Bhalla V. Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice. KIDNEY360 2022; 3:2059-2076. [PMID: 36591362 PMCID: PMC9802554 DOI: 10.34067/kid.0001712022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/19/2022] [Indexed: 01/13/2023]
Abstract
Background Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. Methods Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. Results In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease-promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. Conclusions We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.
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Affiliation(s)
- Xiaoyi Zheng
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Lauren Higdon
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Veterans Affairs Palo Alto Heath Care System, Palo Alto, California
| | - Alexandre Gaudet
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1019-UMR9017-Center for Infection & Immunity of Lille, Pasteur Institute of Lille, University of Lille, Lille, France
| | - Manav Shah
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Angela Balistieri
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Catherine Li
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Patricia Nadai
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1019-UMR9017-Center for Infection & Immunity of Lille, Pasteur Institute of Lille, University of Lille, Lille, France
| | - Latha Palaniappan
- Division of Primary Care and Population Health, Stanford University School of Medicine, Stanford, California
| | - Xiaoping Yang
- Division of Kidney-Urologic Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Briana Santo
- Department of Pathology and Anatomical Sciences, University at Buffalo–The State University of New York, Buffalo, New York
| | - Brandon Ginley
- Department of Pathology and Anatomical Sciences, University at Buffalo–The State University of New York, Buffalo, New York
| | - Xiaoxin X. Wang
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Komuraiah Myakala
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC
| | | | - Moshe Levi
- Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC
| | - Pinaki Sarder
- Department of Pathology and Anatomical Sciences, University at Buffalo–The State University of New York, Buffalo, New York
| | - Avi Rosenberg
- Division of Kidney-Urologic Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jonathan S. Maltzman
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Veterans Affairs Palo Alto Heath Care System, Palo Alto, California
| | - Nathalie de Freitas Caires
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1019-UMR9017-Center for Infection & Immunity of Lille, Pasteur Institute of Lille, University of Lille, Lille, France
- Biothelis, Lille, France
| | - Vivek Bhalla
- Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California
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Mizdrak M, Kumrić M, Kurir TT, Božić J. Emerging Biomarkers for Early Detection of Chronic Kidney Disease. J Pers Med 2022; 12:jpm12040548. [PMID: 35455664 PMCID: PMC9025702 DOI: 10.3390/jpm12040548] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/22/2022] [Accepted: 03/28/2022] [Indexed: 12/14/2022] Open
Abstract
Chronic kidney disease (CKD) is a major and serious global health problem that leads to kidney damage as well as multiple systemic diseases. Early diagnosis and treatment are two major measures to prevent further deterioration of kidney function and to delay adverse outcomes. However, the paucity of early, predictive and noninvasive biomarkers has undermined our ability to promptly detect and treat this common clinical condition which affects more than 10% of the population worldwide. Despite all limitations, kidney function is still measured by serum creatinine, cystatin C, and albuminuria, as well as estimating glomerular filtration rate using different equations. This review aims to provide comprehensive insight into diagnostic methods available for early detection of CKD. In the review, we discuss the following topics: (i) markers of glomerular injury; (ii) markers of tubulointerstitial injury; (iii) the role of omics; (iv) the role of microbiota; (v) and finally, the role of microRNA in the early detection of CKD. Despite all novel findings, none of these biomarkers have met the criteria of an ideal early marker. Since the central role in CKD progression is the proximal tubule (PT), most data from the literature have analyzed biomarkers of PT injury, such as KIM-1 (kidney injury molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), and L-FABP (liver fatty acid-binding protein).
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Affiliation(s)
- Maja Mizdrak
- Department of Nephrology and Hemodialysis, University Hospital of Split, 21000 Split, Croatia;
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (T.T.K.)
| | - Marko Kumrić
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (T.T.K.)
| | - Tina Tičinović Kurir
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (T.T.K.)
- Department of Endocrinology, Diabetes and Metabolic Disorders, University Hospital of Split, 21000 Split, Croatia
| | - Joško Božić
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (T.T.K.)
- Correspondence:
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Denicolò S, Vogi V, Keller F, Thöni S, Eder S, Heerspink HJL, Rosivall L, Wiecek A, Mark PB, Perco P, Leierer J, Kronbichler A, Steger M, Schwendinger S, Zschocke J, Mayer G, Jukic E. Clonal hematopoiesis of indeterminate potential and diabetic kidney disease: a nested case-control study. Kidney Int Rep 2022; 7:876-888. [PMID: 35497780 PMCID: PMC9039487 DOI: 10.1016/j.ekir.2022.01.1064] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/24/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction The disease trajectory of diabetic kidney disease (DKD) shows a high interindividual variability not sufficiently explained by conventional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP) is a proposed novel cardiovascular risk factor. Increased kidney fibrosis and glomerulosclerosis were described in mouse models of CHIP. Here, we aim to analyze whether CHIP affects the incidence or progression of DKD. Methods A total of 1419 eligible participants of the PROVALID Study were the basis for a nested case-control (NCC) design. A total of 64 participants who reached a prespecified composite endpoint within the observation period (initiation of kidney replacement therapy, death from kidney failure, sustained 40% decline in estimated glomerular filtration rate or sustained progression to macroalbuminuria) were identified and matched to 4 controls resulting in an NCC sample of 294 individuals. CHIP was assessed via targeted amplicon sequencing of 46 genes in peripheral blood. Furthermore, inflammatory cytokines were analyzed in plasma via a multiplex assay. Results The estimated prevalence of CHIP was 28.91% (95% CI 22.91%–34.91%). In contrast to other known risk factors (albuminuria, hemoglobin A1c, heart failure, and smoking) and elevated microinflammation, CHIP was not associated with incident or progressive DKD (hazard ratio [HR] 1.06 [95% CI 0.57–1.96]). Conclusions In this NCC study, common risk factors as well as elevated microinflammation but not CHIP were associated with kidney function decline in type 2 diabetes mellitus.
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Aranda-Rivera AK, Srivastava A, Cruz-Gregorio A, Pedraza-Chaverri J, Mulay SR, Scholze A. Involvement of Inflammasome Components in Kidney Disease. Antioxidants (Basel) 2022; 11:246. [PMID: 35204131 PMCID: PMC8868482 DOI: 10.3390/antiox11020246] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 02/01/2023] Open
Abstract
Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.
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Affiliation(s)
- Ana Karina Aranda-Rivera
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Anjali Srivastava
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.S.); (S.R.M.)
| | - Alfredo Cruz-Gregorio
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - José Pedraza-Chaverri
- Laboratory F-315, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico; (A.K.A.-R.); (A.C.-G.); (J.P.-C.)
| | - Shrikant R. Mulay
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.S.); (S.R.M.)
| | - Alexandra Scholze
- Department of Nephrology, Odense University Hospital, Odense, Denmark, and Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark
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Shi C, He A, Wu X, Wang L, Zhu X, Jiang L, Yang J, Zhou Y. Urinary IL-18 is associated with arterial stiffness in patients with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:956186. [PMID: 36263325 PMCID: PMC9574191 DOI: 10.3389/fendo.2022.956186] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/08/2022] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE Diabetic kidney disease (DKD) has been shown to be associated with an excess risk of cardiovascular death. Inflammation has been considered central to type 2 diabetes (T2D) pathophysiology, and inflammation markers have been linked to cardiovascular disease. The serum and urinary IL-18 levels were significantly elevated in patients with T2D; however, whether interleukin 18 (IL-18) are associated with the severity of arterial stiffness remains to be determined. This study examined the relationship of IL-18 levels with pulse wave velocity (PWV) as a reflector for arterial stiffness in patients with T2D. METHODS A total of 180 participants with T2D who had undergone PWV examination were enrolled. Serum and urinary IL-18 levels were measured using sandwich enzyme linked immunosorbent assay (ELISA) kits. Arterial stiffness was determined by carotid-femoral PWV (cf-PWV) and carotid-radial PWV (cr-PWV). RESULTS The urinary IL-18 levels correlated positively with cf-PWV in patients with T2D with DKD (r = 0.418, p < 0.001); however, we found no significant correlation between urinary IL-18 and cf-PWV in diabetic subjects without DKD. In addition, we found no significant correlation between urinary IL-18 and cr-PWV in participants with T2D with or without DKD. Moreover, the association remained significant when controlling for arterial stiffness risk factors, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. cf-PWV was greater in the higher group of urinary IL-18 than in the lower group. Nevertheless, we found no significant correlation between serum IL-18 and cf-PWV in participants with T2D. CONCLUSION The urinary IL-18 levels appear to be associated with greater cf-PWV, suggesting the link between urinary IL-18 and arterial stiffness in patients with T2D.
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Affiliation(s)
| | | | | | | | | | | | | | - Yang Zhou
- *Correspondence: Yang Zhou, ; Junwei Yang,
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Bildaci YD, Bulut H, Elcioglu OC, Gursu M, Kazancioglu R. Alteration of inflammation marker levels with alfa keto analogs in diabetic rats. Niger J Clin Pract 2022; 25:1452-1456. [DOI: 10.4103/njcp.njcp_1868_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Quan KY, Yap CG, Jahan NK, Pillai N. Review of early circulating biomolecules associated with diabetes nephropathy - Ideal candidates for early biomarker array test for DN. Diabetes Res Clin Pract 2021; 182:109122. [PMID: 34742785 DOI: 10.1016/j.diabres.2021.109122] [Citation(s) in RCA: 4] [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: 08/14/2020] [Revised: 07/26/2021] [Accepted: 10/31/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the catastrophic complications of type 2 diabetes mellitus (T2DM). 45% of DN patients progressed to End Stage Renal Disease (ESRD) which robs casualties of the quality of live. The challenge in early diagnosis of DN is it is asymptomatic in the early phase. Current gold standard test for screening and diagnosis of DN are nonspecific and are not sensitive in detecting DN early enough and subsequently monitor renal function during management and intervention plans. Recent studies reported various biomolecules which are associated with the onset of DN in T2DM using cutting-edge technologies. These biomolecules could be potential early biomarkers for DN. This review selectively identified potential early serum biomolecules which are potential candidates for developing an Early Biomarker Array Test for DN. METHODS An advanced literature search was conducted on 4 online databases. Search terms used were "Diabetes Mellitus, Type 2", "Diabetic nephropathy", "pathogenesis" and "early biomarker. Filters were applied to capture articles published from 2010 to 2020, written in English, human or animal models and focused on serum biomolecules associated with DN. RESULTS Five serum biomolecules have been evidently described as contributing pivotal roles in the pathophysiology of DN. MiR-377, miR-99b, CYP2E1, TGF-β1 and periostin are potential candidates for designing an early biomarker array for screening and diagnosis of early stages of DN. The five shortlisted biomolecules originates from endogenous biochemical processes which are specific to the progressive pathophysiology of DN. CONCLUSION miR-377, miR-99b, CYP2E1, TGF-β1 and periostin are potential candidate biomolecules for diagnosing DN at the early phases and can be developed into a panel of endogenous biomarkers for early detection of DN in patients with T2DM. The outcomes of this study will be a stepping stone towards planning and developing an early biomarker array test for diabetic nephropathy. The proposed panel of early biomarkers for DN has potential of stratifying the stages of DN because each biomolecule appears at distinct stages in the pathophysiology of DN.
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Affiliation(s)
- Kok Ying Quan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia
| | - Christina Gertrude Yap
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
| | - Nowrozy Kamar Jahan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
| | - Naganathan Pillai
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Kuala Lumpur, Malaysia.
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Abstract
Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease for over 20 years. Yet, over these two decades, the clinical approach to this condition has not much improved beyond the administration of glucose-lowering agents, renin-angiotensin-aldosterone system blockers for blood pressure control, and lipid-lowering agents. The proportion of diabetic patients who develop DKD and progress to end-stage renal disease has remained nearly the same. This unmet need for DKD treatment is caused by the complex pathophysiology of DKD, and the difficulty of translating treatment from bench to bed, which further adds to the growing argument that DKD is not a homogeneous disease. To better capture the full spectrum of DKD in our design of treatment regimens, we need improved diagnostic tools that can better distinguish the subgroups within the condition. For instance, DKD is typically placed in the broad category of a non-inflammatory kidney disease. However, genome-wide transcriptome analysis studies consistently indicate the inflammatory signaling pathway activation in DKD. This review will utilize human data in discussing the potential for redefining the role of inflammation in DKD. We also comment on the therapeutic potential of targeted anti-inflammatory therapy for DKD.
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Affiliation(s)
- Su Woong Jung
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
- Correspondence to Ju-Young Moon, M.D. Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea Tel: +82-2-440-7064 Fax: +82-2-440-8150 E-mail:
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Nicholas SB. Novel Anti-inflammatory and Anti-fibrotic Agents for Diabetic Kidney Disease-From Bench to Bedside. Adv Chronic Kidney Dis 2021; 28:378-390. [PMID: 34922694 DOI: 10.1053/j.ackd.2021.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/30/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023]
Abstract
Chronic low-grade inflammation, now coined by the new paradigm as "metaflammation" or "metainflammation", has been linked to chronic kidney disease and its progression. In diabetes, altered metabolism denotes factors associated with the metabolic syndrome and hyperglycemia, among others. The interplay among hyperglycemia, oxidative stress, and inflammation in the pathogenesis of diabetic kidney disease (DKD) has been broadly explored. Identification of mediators of inflammatory processes involving macrophage infiltration, production of inflammasomes, release of cytokines, and activation of pertinent signaling pathways including mitogen-activated protein kinase, Jun N-terminal kinase, Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (JAK/STAT), and apoptosis signal-regulating kinase 1 signaling mechanisms have enabled the development of therapeutic agents for DKD. This review describes the evidence supporting the contribution of the inflammatory response and fibrotic changes and focuses on selected, novel, promising drugs as well as repurposed drugs that have made it to phase 2, 3, or 4 of clinical trials in adults with type 2 diabetes mellitus and their potential to become an important part of our armamentarium to improve the management of DKD. Importantly, drugs that solely target inflammatory processes may be insufficient to fully optimize care of patients with DKD because of the complex nature of the disease.
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Hirooka Y, Nozaki Y. Interleukin-18 in Inflammatory Kidney Disease. Front Med (Lausanne) 2021; 8:639103. [PMID: 33732720 PMCID: PMC7956987 DOI: 10.3389/fmed.2021.639103] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/08/2021] [Indexed: 12/29/2022] Open
Abstract
Interleukin (IL)-18, a member of the IL-1 superfamily, is a pro-inflammatory cytokine that is structurally similar to IL-1β. IL-18 promotes the production of interferon gamma (IFN-γ) and strongly induces a Th1 response. IL-18 drives the same myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway as IL-1β. In physiological conditions, IL-18 is regulated by the endogenous inhibitor IL-18 binding protein (IL-18BP), and the activity of IL-18 is balanced. It is reported that in several inflammatory diseases, the IL-18 activity is unbalanced, and IL-18 neutralization by IL-18BP is insufficient. IL-18 acts synergistically with IL-12 to induce the production of IFN-γ as a Th1 cytokine, and IL-18 acts alone to induce the production of Th2 cytokines such as IL-4 and IL-13. In addition, IL-18 alone enhances natural killer (NK) cell activity and FAS ligand expression. The biological and pathological roles of IL-18 have been studied in many diseases. Here we review the knowledge regarding IL-18 signaling and the role of IL-18 in inflammatory kidney diseases. Findings on renal injury in coronavirus disease 2019 (COVID-19) and its association with IL-18 will also be presented.
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Affiliation(s)
- Yasuaki Hirooka
- Department of Rheumatology, Kindai University Nara Hospital, Nara, Japan
| | - Yuji Nozaki
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
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Liu P, Zhang Z, Li Y. Relevance of the Pyroptosis-Related Inflammasome Pathway in the Pathogenesis of Diabetic Kidney Disease. Front Immunol 2021; 12:603416. [PMID: 33692782 PMCID: PMC7937695 DOI: 10.3389/fimmu.2021.603416] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD) in many developed and developing countries. Pyroptosis is a recently discovered form of programmed cell death (PCD). With progress in research on DKD, researchers have become increasingly interested in elucidating the role of pyroptosis in DKD pathogenesis. This review focuses on the three pathways of pyroptosis generation: the canonical inflammasome, non-canonical inflammasome, and caspase-3-mediated inflammasome pathways. The molecular and pathophysiological mechanisms of the pyroptosis-related inflammasome pathway in the development of DKD are summarized. Activation of the diabetes-mediated pyroptosis-related inflammasomes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Toll-like receptor 4 (TLR4), caspase-1, interleukin (IL)-1β, and the IL-18 axis, plays an essential role in DKD lesions. By inhibiting activation of the TLR4 and NLRP3 inflammasomes, the production of caspase-1, IL-1β, and IL-18 is inhibited, thereby improving the pathological changes associated with DKD. Studies using high-glucose-induced cell models, high-fat diet/streptozotocin-induced DKD animal models, and human biopsies will help determine the spatial and temporal expression of DKD inflammatory components. Recent studies have confirmed the relationship between the pyroptosis-related inflammasome pathway and kidney disease. However, these studies are relatively superficial at present, and the mechanism needs further elucidation. Linking these findings with disease activity and prognosis would provide new ideas for DKD research.
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Affiliation(s)
- Pan Liu
- Department of Endocrinology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Zhengdong Zhang
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Yao Li
- Department of Endocrinology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
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Leaf Extracts of Anchomanes difformis Ameliorated Kidney and Pancreatic Damage in Type 2 Diabetes. PLANTS 2021; 10:plants10020300. [PMID: 33562428 PMCID: PMC7914445 DOI: 10.3390/plants10020300] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/28/2022]
Abstract
Kidney disease in diabetes is one of the common microvascular complications of diabetes mellitus implicated in end-stage renal failure. This study explored the ability of Anchomanes difformis to ameliorate kidney and pancreatic damage in type 2 diabetes mellitus using male Wistar rats. Two weeks of fructose (10%) administration followed by streptozotocin (40 mg/kg) were used to induce type 2 diabetes. Leaf extract (aqueous) of Anchomanes difformis (200 mg and 400 mg/kgBW) was administered orally for six weeks. Body weights were monitored, urea and creatinine were measured. Interleukins (IL)-1β, IL-6, IL-10, IL-18, and TNFα were measured in the kidney lysate. CAT, SOD, ORAC, FRAP, and MDA levels were also evaluated in the kidney. Transcription factors (Nrf2 and NF-ĸB/p65) and apoptotic markers (Bcl2 and caspase 3) were investigated in the kidney. Histological sections of the pancreas and kidney tissues were examined for any visible pathology. Supplementation with Anchomanesdifformis enhanced antioxidant status, modulated inflammatory response, and reduced apoptosis in the kidney. It also restored the kidney and pancreatic histoarchitecture of the treated diabetic rats. The pathophysiology associated with diabetic nephropathy and pancreatic damage showcase the importance of exploring the use of antidiabetic, nephroprotective agents such as Anchomanes difformis to kidney damage in type 2 diabetes.
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Kidney failure risk in type 1 vs. type 2 childhood-onset diabetes mellitus. Pediatr Nephrol 2021; 36:333-340. [PMID: 32761484 DOI: 10.1007/s00467-020-04631-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/29/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is becoming increasingly common among children. We aimed to estimate the risk of end-stage renal disease (ESKD) and mortality among adolescents with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and normal renal function compared with non-diabetics. We hypothesized that childhood onset T1DM vs. T2DM would be associated with a different risk profile for developing ESKD and its complications. METHODS A nationwide, population-based, retrospective cohort study, including 1,500,522 adolescents examined for military service between 1967 and 1997, which were classified according to the presence and type of diabetes. Data were linked to the Israeli ESKD registry. Cox proportional-hazards models were used to estimate the hazard ratio (HR) for ESKD. RESULTS At study enrolment, 1183 adolescents had T1DM and 196 had T2DM. ESKD developed in 2386 non-diabetic individuals (0.2%) compared with 72 individuals (6.1%) with T1DM and 8 individuals (4.1%) with T2DM. Participants with T1DM were younger at ESKD onset than participants with T2DM (median age, 36.0 vs. 40.5 years, P < 0.05). In a multivariate model adjusted for age, sex, paternal origin, enrollment year, BMI, and blood pressure, T1DM and T2DM were associated with HR of 36.4 (95% CI 28.3-46.9) and 19.3 (95% CI 9.6-38.8) for ESKD, respectively. Stratification according to sex, ethnicity, immigration, and socioeconomic status did not materially change the HR. During the follow-up period, mortality rates were higher in T2DM as compared with T1DM and controls (8.7 %, 2.2%, and 2.7% respectively). CONCLUSIONS T1DM and T2DM in adolescents with normal renal function confer a significantly increased risk for ESKD. T1DM is associated with younger age at ESKD onset while T2DM is associated with higher mortality rate.
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Donate-Correa J, Ferri CM, Sánchez-Quintana F, Pérez-Castro A, González-Luis A, Martín-Núñez E, Mora-Fernández C, Navarro-González JF. Inflammatory Cytokines in Diabetic Kidney Disease: Pathophysiologic and Therapeutic Implications. Front Med (Lausanne) 2021; 7:628289. [PMID: 33553221 PMCID: PMC7862763 DOI: 10.3389/fmed.2020.628289] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/24/2020] [Indexed: 12/29/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and a main contributing factor for cardiovascular morbidity and mortality in patients with diabetes mellitus. Strategies employed to delay the progression of this pathology focus on the control of traditional risk factors, such as hyperglycemia, and elevated blood pressure. Although the intimate mechanisms involved in the onset and progression of DKD remain incompletely understood, inflammation is currently recognized as one of the main underlying processes. Untangling the mechanisms involved in the appearing of a harmful inflammatory response in the diabetic patient is crucial for the development of new therapeutic strategies. In this review, we focus on the inflammation-related pathogenic mechanisms involved in DKD and in the therapeutic utility of new anti-inflammatory strategies.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
| | - Carla M. Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Fátima Sánchez-Quintana
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Atteneri Pérez-Castro
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ainhoa González-Luis
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Spain
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- GEENDIAB (Grupo Español para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain
- REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain
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Guest PC. The Impact of New Biomarkers and Drug Targets on Age-Related Disorders. Methods Mol Biol 2020; 2138:3-28. [PMID: 32219738 DOI: 10.1007/978-1-0716-0471-7_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The increase in the human lifespan has not been paralleled by an increase in healthy life. With the increase in the proportion of the aged population, there has been a natural increase in the prevalence of age-related disorders, such as Alzheimer's disease, type 2 diabetes mellitus, frailty, and various other disorders. A continuous rise in these conditions could lead to a widespread medical and social burden. There are now considerable efforts underway to address these deficits in preclinical and clinical studies, which include the use of better study cohorts, longitudinal designs, improved translation of data from preclinical models, multi-omics profiling, identification of new biomarker candidates and refinement of computational tools and databases containing relevant information. Such efforts will support future interdisciplinary studies and help to identify potential new targets that are amenable to therapeutic approaches such as pharmacological interventions to increase the human healthspan in parallel with the lifespan.
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Affiliation(s)
- Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
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21
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Petrica L, Milas O, Vlad M, Vlad A, Gadalean F, Dumitrascu V, Velciov S, Gluhovschi C, Bob F, Ursoniu S, Jianu DC, Matusz P, Pusztai AM, Cretu O, Radu D, Secara A, Simulescu A, Stefan M, Popescu R, Vlad D. Interleukins and miRNAs intervene in the early stages of diabetic kidney disease in Type 2 diabetes mellitus patients. Biomark Med 2019; 13:1577-1588. [PMID: 31663375 DOI: 10.2217/bmm-2019-0124] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Aim: The involvement of proinflammatory interleukins (IL) in diabetic kidney disease of Type 2 diabetes mellitus (DM) patients was studied in relation to a particular miRNA profile. Materials & methods: A total of 117 patients with Type 2 DM and 11 controls were enrolled in a case series study. Serum and urinary ILs and miRNAs were assessed. Results: IL-1α correlated with miRNA21, 124, estimated glomerular filtration rate (eGFR) and negatively with miRNA125a and 192; IL-8 with miRNA21, 124, eGFR and negatively with miRNA125a, 126 and 146a; IL-18 with miRNA21, 124 and negatively with miRNA146a, 192, eGFR. Conclusion: There is an association between specific serum and urinary ILs and serum and urinary miRNAs profiles in the inflammatory response in Type 2 DM patients with diabetic kidney disease.
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Affiliation(s)
- Ligia Petrica
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania.,Centre of Translational Research & Systems Medicine, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Oana Milas
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Mihaela Vlad
- Department of Endocrinology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Adrian Vlad
- Department of Diabetes & Metabolic Diseases, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Florica Gadalean
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Victor Dumitrascu
- Department of Pharmacology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Silvia Velciov
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Cristina Gluhovschi
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Flaviu Bob
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Sorin Ursoniu
- Centre of Translational Research & Systems Medicine, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania.,Department of Public Health Medicine, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Dragos C Jianu
- Department of Neurology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Petru Matusz
- Department of Anatomy & Embryology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Agneta-Maria Pusztai
- Department of Anatomy & Embryology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Octavian Cretu
- Department of Surgery I, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Daniela Radu
- Department of Surgery II, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Alina Secara
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Anca Simulescu
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Maria Stefan
- Department of Nephrology, 'Victor Babes' University of Medicine & Pharmacy, Romania
| | - Roxana Popescu
- Department of Cellular & Molecular Biology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
| | - Daliborca Vlad
- Department of Pharmacology, 'Victor Babes' University of Medicine & Pharmacy, 300041 Timisoara, Romania
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22
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Al-Rubeaan K, Nawaz SS, Youssef AM, Al Ghonaim M, Siddiqui K. IL-18, VCAM-1 and P-selectin as early biomarkers in normoalbuminuric Type 2 diabetes patients. Biomark Med 2019; 13:467-478. [PMID: 31169028 DOI: 10.2217/bmm-2018-0359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To investigate the pathophysiological role of different biomarkers in diabetic kidney disease (DKD) among normoalbuminuric patients with a low-estimated glomerular filtration rate (eGFR). Methods: In this cross-sectional study of 200 normoalbuminuric Type 2 diabetes patients, 28 patients (14%) had a low eGFR. Results: The IL-18, VCAM-1 and P-selectin levels were significantly higher at a low eGFR. On analyzing the area under the receiver operating characteristic curve, these biomarkers had significant diagnostic value and have important pathophysiological role in the progression of DKD. Conclusion: Among normoalbuminuric Type 2 diabetes patients, IL-18, VCAM-1 and P-selectin may play a significant role in the prediction of early DKD. Further prospective studies need to be conducted to confirm this observation.
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Affiliation(s)
- Khalid Al-Rubeaan
- Department of Medicine, University Diabetes Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Shaik S Nawaz
- Biochemistry Department, Strategic Center for Diabetes Research, King Saud University, Riyadh, Saudi Arabia
| | - Amira M Youssef
- Biochemistry Department, Registry Department, University Diabetes Center, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Al Ghonaim
- College of Medicine, King Khalid Universe Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Khalid Siddiqui
- Biochemistry Department, Strategic Center for Diabetes Research, King Saud University, Riyadh, Saudi Arabia
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23
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Niewczas MA, Pavkov ME, Skupien J, Smiles A, Md Dom ZI, Wilson JM, Park J, Nair V, Schlafly A, Saulnier PJ, Satake E, Simeone CA, Shah H, Qiu C, Looker HC, Fiorina P, Ware CF, Sun JK, Doria A, Kretzler M, Susztak K, Duffin KL, Nelson RG, Krolewski AS. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med 2019; 25:805-813. [PMID: 31011203 PMCID: PMC6508971 DOI: 10.1038/s41591-019-0415-5] [Citation(s) in RCA: 288] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 03/07/2019] [Indexed: 12/20/2022]
Abstract
Chronic inflammation is postulated to be involved in development of end stage renal disease (ESRD) in diabetes, but which specific circulating inflammatory proteins contribute to this risk remains unknown. To study this we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with Type 1 and Type 2 diabetes. In each cohort we identified an extremely robust Kidney Risk Inflammatory Signature (KRIS) consisting of 17 novel proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of ESRD. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying ESRD development in both types of diabetes. These proteins may be used as new therapeutic targets, new prognostic tests for high risk of ESRD and as surrogate outcome measures where changes in KRIS levels during intervention can reflect the tested therapy’s effectiveness. Proteomic profiling of circulating proteins in subjects from three independent cohorts with type 1 and type 2 diabetes, identified an extremely robust inflammatory signature, consisting of 17 proteins enriched for TNF Receptor Superfamily members that was associated with a 10-year risk of end-stage renal disease.
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Affiliation(s)
- Monika A Niewczas
- Research Division, Joslin Diabetes Center, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Meda E Pavkov
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jan Skupien
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Adam Smiles
- Research Division, Joslin Diabetes Center, Boston, MA, USA
| | - Zaipul I Md Dom
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jonathan M Wilson
- Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Jihwan Park
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Viji Nair
- Nephrology/Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | | | - Pierre-Jean Saulnier
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA.,CHU Poitiers, University of Poitiers, Inserm, Clinical Investigation Center CIC1402, Poitiers, France
| | - Eiichiro Satake
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Hetal Shah
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Chengxiang Qiu
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Helen C Looker
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Romeo ed Enrica Invernizzi Pediatric Center, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Carl F Ware
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Jennifer K Sun
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Matthias Kretzler
- Nephrology/Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Katalin Susztak
- Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kevin L Duffin
- Diabetes and Complications Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Robert G Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Andrzej S Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA.
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24
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Angelova P, Kamenov Z, Tsakova A, El-Darawish Y, Okamura H. Interleukin-18 and testosterone levels in men with metabolic syndrome. Aging Male 2018; 21:130-137. [PMID: 29168426 DOI: 10.1080/13685538.2017.1401993] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Interleukin 18 (IL-18) is an adipokine associated with obesity. Data about the relationship of IL-18 to the metabolic syndrome (MS) are still scarce. Low testosterone (T) levels are common in men with MS, but we did not find data about the levels of IL-18 in men with low T. The aim of this study was to determine the levels of IL-18 in men with MS with or without low T. PATIENTS AND METHODS A total of 251 men were included in the study. Of them 218 had MS (IDF 2005) and they were divided according to their morning total testosterone (TT) level (cutoff 10.4 nmol/l) into two groups: MS-low T (N = 84) and MS-normal T (N = 134). The control group consisted of 33 men without MS and low T. IL-18 was determined in serum using enzyme-linked immunosorbent assay. A small group of eight men with MS and low T levels received testosterone therapy for three months and physical and laboratory parameters were monitored at the end of that period. RESULTS MS men were at mean age (±SD) = 53.77 ± 9.59 years; body mass index (BMI) = 34.0 ± 6.3 kg/m2; and TT = 12.59 ± 5.66 nmol/l. The control group was at age = 52.12 ± 5.2 years (NS); BMI = 25.6 ± 2.4 kg/m2 (p < .001); and TT = 17.8 ± 5.68 nmol/l (p < .001), respectively. The levels of IL-18 were higher in the MS group - 345 pg/ml compared to the control one - 264 pg/ml (p < .01). There was no significant difference between MS-low T (330.6 pg/ml) and MS-normal T (350.2 pg/ml) subgroups. The MS-normal T differed more significantly from the control group (p < .001). Significant correlation of testosterone with IL-18 levels was not found. IL-18 correlated with parameters of obesity, lipids, fasting blood sugar (p < .05) and the number of criteria for MS (p < .001). Three months on T treatment showed improvement in obesity parameters and only in one patient IL-18 had clear reduction while the rest showed no change. CONCLUSIONS In this study, higher IL-18 levels were found in the presence of MS compared to healthy men, but they did not differ between men having MS with or without LOH.
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Affiliation(s)
- Petya Angelova
- a Clinic of Endocrinology , Alexandrovska University Hospital, Medical University-Sofia , Sofia , Bulgaria
| | - Zdravko Kamenov
- a Clinic of Endocrinology , Alexandrovska University Hospital, Medical University-Sofia , Sofia , Bulgaria
| | - Adelina Tsakova
- b Central Clinical Laboratory , Alexandrovska University Hospital, Medical University-Sofia , Sofia , Bulgaria
| | - Yosif El-Darawish
- c Laboratory of Tumor Immunology and Immunotherapy , Hyogo College of Medicine , Hyogo , Japan
| | - Haruki Okamura
- d Laboratory of Host Defense , Hyogo College of Medicine , Hyogo , Japan
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25
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Alicic RZ, Johnson EJ, Tuttle KR. Inflammatory Mechanisms as New Biomarkers and Therapeutic Targets for Diabetic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:181-191. [PMID: 29580582 DOI: 10.1053/j.ackd.2017.12.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/08/2023]
Abstract
Diabetic kidney disease (DKD) is the leading cause of CKD and end-stage kidney disease (ESKD) worldwide. Approximately 30-40% of people with diabetes develop this microvascular complication, placing them at high risk of losing kidney function as well as of cardiovascular events, infections, and death. Current therapies are ineffective for arresting kidney disease progression and mitigating risks of comorbidities and death among patients with DKD. As the global count of people with diabetes will soon exceed 400 million, the need for effective and safe treatment options for complications such as DKD becomes ever more urgent. Recently, the understanding of DKD pathogenesis has evolved to recognize inflammation as a major underlying mechanism of kidney damage. In turn, inflammatory mediators have emerged as potential biomarkers and therapeutic targets for DKD. Phase 2 clinical trials testing inhibitors of monocyte-chemotactic protein-1 chemokine C-C motif-ligand 2 and the Janus kinase/signal transducer and activator of transcription pathway, in particular, have produced promising results.
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26
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Jhun MA, Smith JA, Ware EB, Kardia SLR, Mosley TH, Turner ST, Peyser PA, Park SK. Modeling the Causal Role of DNA Methylation in the Association Between Cigarette Smoking and Inflammation in African Americans: A 2-Step Epigenetic Mendelian Randomization Study. Am J Epidemiol 2017; 186:1149-1158. [PMID: 29149250 DOI: 10.1093/aje/kwx181] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 01/17/2017] [Indexed: 01/17/2023] Open
Abstract
The association between cigarette smoking and inflammation is well known. However, the biological mechanisms behind the association are not fully understood, particularly the role of DNA methylation, which is known to be affected by smoking. Using 2-step epigenetic Mendelian randomization, we investigated the role of DNA methylation in the association between cigarette smoking and inflammation. In 822 African Americans from the Genetic Epidemiology Network of Arteriopathy, phase 2 (Jackson, Mississippi; 2000-2005), study population, we examined the association of cigarette smoking with DNA methylation using single nucleotide polymorphisms identified in previous genome-wide association studies of cigarette smoking. We then investigated the association of DNA methylation with levels of inflammatory markers using cis-methylation quantitative trait loci single nucleotide polymorphisms. We found that current smoking status was associated with the DNA methylation levels (M values) of cg03636183 in the coagulation factor II (thrombin) receptor-like 3 gene (F2RL3) (M = -0.64, 95% confidence interval (CI): -0.84, -0.45) and of cg19859270 in the G protein-coupled receptor 15 gene (GPR15) (M = -0.21, 95% CI: -0.27, -0.15). The DNA methylation levels of cg03636183 in F2RL3 were associated with interleukin-18 concentration (-0.11 pg/mL, 95% CI: -0.19, -0.04). These combined negative effects suggest that cigarette smoking increases interleukin-18 levels through the decrease in DNA methylation levels of cg03636183 in F2RL3.
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27
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Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal Physiol 2017; 312:F716-F731. [PMID: 27558558 PMCID: PMC6109808 DOI: 10.1152/ajprenal.00314.2016] [Citation(s) in RCA: 196] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/16/2016] [Indexed: 01/10/2023] Open
Abstract
Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.
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Affiliation(s)
- Raimund Pichler
- Division of Nephrology, University of Washington, Seattle, Washington;
| | - Maryam Afkarian
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
| | - Brad P Dieter
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
| | - Katherine R Tuttle
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
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28
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Fakhruddin S, Alanazi W, Jackson KE. Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury. J Diabetes Res 2017; 2017:8379327. [PMID: 28164134 PMCID: PMC5253173 DOI: 10.1155/2017/8379327] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 12/07/2016] [Indexed: 02/07/2023] Open
Abstract
Diabetes induces the onset and progression of renal injury through causing hemodynamic dysregulation along with abnormal morphological and functional nephron changes. The most important event that precedes renal injury is an increase in permeability of plasma proteins such as albumin through a damaged glomerular filtration barrier resulting in excessive urinary albumin excretion (UAE). Moreover, once enhanced UAE begins, it may advance renal injury from progression of abnormal renal hemodynamics, increased glomerular basement membrane (GBM) thickness, mesangial expansion, extracellular matrix accumulation, and glomerulosclerosis to eventual end-stage renal damage. Interestingly, all these pathological changes are predominantly driven by diabetes-induced reactive oxygen species (ROS) and abnormal downstream signaling molecules. In diabetic kidney, NADPH oxidase (enzymatic) and mitochondrial electron transport chain (nonenzymatic) are the prominent sources of ROS, which are believed to cause the onset of albuminuria followed by progression to renal damage through podocyte depletion. Chronic hyperglycemia and consequent ROS production can trigger abnormal signaling pathways involving diverse signaling mediators such as transcription factors, inflammatory cytokines, chemokines, and vasoactive substances. Persistently, increased expression and activation of these signaling molecules contribute to the irreversible functional and structural changes in the kidney resulting in critically decreased glomerular filtration rate leading to eventual renal failure.
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Affiliation(s)
- Selim Fakhruddin
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Pharmacy Building, 1800 Bienville Dr., Monroe, LA 71201, USA
| | - Wael Alanazi
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Pharmacy Building, 1800 Bienville Dr., Monroe, LA 71201, USA
| | - Keith E. Jackson
- Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe (ULM), Pharmacy Building, 1800 Bienville Dr., Monroe, LA 71201, USA
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29
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Ozanne SE, Rahmoune H, Guest PC. Multiplex Biomarker Approaches in Type 2 Diabetes Mellitus Research. Methods Mol Biol 2017; 1546:37-55. [PMID: 27896756 DOI: 10.1007/978-1-4939-6730-8_3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus is a multifactorial condition resulting in high fasting blood glucose levels. Although its diagnosis is straightforward, there is not one set of biomarkers or drug targets that can be used for classification or personalized treatment of individuals who suffer from this condition. Instead, the application of multiplex methods incorporating a systems biology approach is essential in order to increase our understanding of this disease. This chapter reviews the state of the art in biomarker studies of human type 2 diabetes from a proteomic and metabolomic perspective. Our main focus was on biomarkers for disease prediction as these could lead to early intervention strategies for the best possible patient outcomes.
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Affiliation(s)
- Susan E Ozanne
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. .,Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QR, UK.
| | - Hassan Rahmoune
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Pembroke Street, Cambridge, UK
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
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30
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Qiu YY, Tang LQ. Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy. Pharmacol Res 2016; 114:251-264. [PMID: 27826011 DOI: 10.1016/j.phrs.2016.11.004] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/10/2016] [Accepted: 11/03/2016] [Indexed: 12/22/2022]
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and persistent inflammation in circulatory and renal tissues is an important pathophysiological basis for DN. The essence of the microinflammatory state is the innate immune response, which is central to the occurrence and development of DN. Members of the inflammasome family, including both "receptors" and "regulators", are key to the inflammatory immune response. Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and other inflammasome components are able to detect endogenous danger signals, resulting in activation of caspase-1 as well as interleukin (IL)-1β, IL-18 and other cytokines; these events stimulate the inflammatory cascade reaction, which is crucial for DN. Hyperglycaemia, hyperlipidaemia and hyperuricaemia can activate the NLRP3 inflammasome, which then mediates the occurrence and development of DN through the K+ channel model, the lysosomal damage model and the active oxygen cluster model. In this review, we survey the involvement of the NLRP3 inflammasome in various signalling pathways and highlight different aspects of their influence on DN. We also explore the important effects of the NLRP3 inflammasome on kidney function and structural changes that occur during DN development and progression. It is becoming more evident that NLRP3 inflammasome targeting has therapeutic potential for the treatment of DN.
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Affiliation(s)
- Yuan-Ye Qiu
- Anhui Provincial Hospital, Anhui Medical University, 17# Lu-jiang Road, Hefei 230001, Anhui, China.
| | - Li-Qin Tang
- Anhui Provincial Hospital, Anhui Medical University, 17# Lu-jiang Road, Hefei 230001, Anhui, China.
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31
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Sun Y, Peng R, Peng H, Liu H, Wen L, Wu T, Yi H, Li A, Zhang Z. miR-451 suppresses the NF-kappaB-mediated proinflammatory molecules expression through inhibiting LMP7 in diabetic nephropathy. Mol Cell Endocrinol 2016; 433:75-86. [PMID: 27264074 DOI: 10.1016/j.mce.2016.06.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/31/2016] [Accepted: 06/02/2016] [Indexed: 10/21/2022]
Abstract
Activation of nuclear factor -kappa B (NF-κB) is associated with inflammation in the progression of diabetic nephropathy (DN). MiR-451 is closely linked to renal damage in DN. Large multifunctional protease 7 (LMP7), an immunoproteasome subunit, can activate NF-κB. However, it remained unclear whether miR-451 affected NF-κB-induced inflammation by regulating LMP7 in DN. In this study, deep sequencing, in situ hybridization, quantitative real-time PCR, dual-luciferase reporter gene assays, western blot and chromatin immunoprecipitation were respectively used. For the results, we found that miR-451 was markedly downregulated in the kidneys of db/db mice, PBMCs of DN patients and mesangial cells (MCs) cultured in high glucose conditions. Furthermore, miR-451 directly targeted LMP7 expression to inhibit NF-κB activity, and down-regulated transcription of proinflammatory molecules in MCs. More importantly, in the kidneys of db/db DN mice, increasing miR-451 level inhibited LMP7/NF-κB activity, and attenuated the urinary microalbumin excretion, blood glucose, and glomerular injury. In conclusion, these results provide new insights into the regulation of miR-451 via the LMP7/NF-κB central inflammatory pathway during progression of DN.
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Affiliation(s)
- Yan Sun
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | - Rui Peng
- Department of Bioinformatics, Chongqing Medical University, Chongqing 400016, China
| | - Huimin Peng
- Experimental Teaching Center, Chongqing Medical University, Chongqing 400016, China
| | - Handeng Liu
- Experimental Teaching Center, Chongqing Medical University, Chongqing 400016, China
| | - Li Wen
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | - Tianhui Wu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | - Hong Yi
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | - Ailing Li
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | - Zheng Zhang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China.
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Lopes-Virella MF, Hunt KJ, Baker NL, Virella G. High levels of AGE-LDL, and of IgG antibodies reacting with MDA-lysine epitopes expressed by oxLDL and MDA-LDL in circulating immune complexes predict macroalbuminuria in patients with type 2 diabetes. J Diabetes Complications 2016; 30:693-9. [PMID: 26861948 DOI: 10.1016/j.jdiacomp.2016.01.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 01/11/2016] [Accepted: 01/12/2016] [Indexed: 02/03/2023]
Abstract
BACKGROUND Circulating immune complexes (IC) containing modified forms of LDL (mLDL) are strongly pro-inflammatory and when present in high levels are associated with the development of diabetic complications. OBJECTIVE We investigated whether levels of oxidized LDL (oxLDL), malondialdehyde-LDL (MDA-LDL) and advanced glycation end products-LDL (AGE-LDL) as well as IgG and IgM antibodies reacting with MDA-lysine epitopes expressed by oxLDL and MDA-LDL isolated from circulating IC were associated with progression to macroalbuminuria in type 2 diabetes (VADT cohort). METHODS Levels of mLDL in IC were measured in 905 patients, a median of two years after entry into the study. Participants were followed for an average of 3.7years for renal outcomes. Generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, persistent micro- (ACR ≥30), incident micro- (ACR ≥30) and incident macroalbuminuria (ACR ≥300) were the outcomes of interest. RESULTS AND CONCLUSIONS Patients with macro (n=78) or non-persistent microalbuminuria (n=81) at baseline were excluded. Odds ratios for endpoints in relation to high versus low (defined using a median split) biomarker levels are found in Fig. 1. Our study demonstrates that high levels of AGE-LDL as well as of IgG antibodies (but not IgM antibodies) reacting with MDA-LDL lysine epitopes in circulating IC predict the development of macroalbuminuria in patients with type 2 diabetes. These data support the pathogenic role of modified LDL IgG antibodies but not the protective role of modified LDL IgM antibodies.
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Affiliation(s)
- Maria F Lopes-Virella
- Department of Medicine and Laboratory Services, Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC.
| | - Kelly J Hunt
- Department of Public Health Services, Medical University of South Carolina, Charleston, SC
| | - Nathaniel L Baker
- Department of Public Health Services, Medical University of South Carolina, Charleston, SC
| | - Gabriel Virella
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
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McKie EA, Reid JL, Mistry PC, DeWall SL, Abberley L, Ambery PD, Gil-Extremera B. A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus. PLoS One 2016; 11:e0150018. [PMID: 26930607 PMCID: PMC4773233 DOI: 10.1371/journal.pone.0150018] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 02/08/2016] [Indexed: 11/23/2022] Open
Abstract
Objective Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed. Research Design and Methods This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18–70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0–4 hours) postmixed meal test on Days 29, 57, and 85. Results Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0–4 hours) compared with placebo. Conclusions GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded. Trial Registration ClinicalTrials.gov NCT01648153
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Affiliation(s)
| | - Juliet L. Reid
- Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | | | - Stephen L. DeWall
- Clinical Immunology, Biopharm R&D, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Lee Abberley
- Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Philip D. Ambery
- GlaxoSmithKline, Clinical development, Cardiovascular and Metabolic Medicines Development Centre, London, United Kingdom
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Elsherbiny NM, Al-Gayyar MMH. The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 2016; 81:15-22. [PMID: 26836949 DOI: 10.1016/j.cyto.2016.01.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 01/24/2016] [Indexed: 12/18/2022]
Abstract
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Nehal M Elsherbiny
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
| | - Mohammed M H Al-Gayyar
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
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Zhang L, Zhang L, Li Y, Guo XF, Liu XS. Biotransformation effect of Bombyx Mori L. may play an important role in treating diabetic nephropathy. Chin J Integr Med 2015; 22:872-879. [DOI: 10.1007/s11655-015-2128-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Indexed: 10/22/2022]
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Tziomalos K, Athyros VG. Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis. Rev Diabet Stud 2015; 12:110-118. [PMID: 26676664 PMCID: PMC5397986 DOI: 10.1900/rds.2015.12.110] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 04/30/2015] [Accepted: 04/30/2015] [Indexed: 12/23/2022] Open
Abstract
Diabetic nephropathy is the leading cause of end-stage renal disease. Patients with diabetic nephropathy have a high cardiovascular risk, comparable to patients with coronary heart disease. Accordingly, identification and management of risk factors for diabetic nephropathy as well as timely diagnosis and prompt management of the condition are of paramount importance for effective treatment. A variety of risk factors promotes the development and progression of diabetic nephropathy, including elevated glucose levels, long duration of diabetes, high blood pressure, obesity, and dyslipidemia. Most of these risk factors are modifiable by antidiabetic, antihypertensive, or lipid-lowering treatment and lifestyle changes. Others such as genetic factors or advanced age cannot be modified. Therefore, the rigorous management of the modifiable risk factors is essential for preventing and delaying the decline in renal function. Early diagnosis of diabetic nephropathy is another essential component in the management of diabetes and its complications such as nephropathy. New markers may allow earlier diagnosis of this common and serious complication, but further studies are needed to clarify their additive predictive value, and to define their cost-benefit ratio. This article reviews the most important risk factors in the development and progression of diabetic nephropathy and summarizes recent developments in the diagnosis of this disease.
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Affiliation(s)
- Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Vasilios G. Athyros
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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Shikata K, Makino H. Microinflammation in the pathogenesis of diabetic nephropathy. J Diabetes Investig 2014; 4:142-9. [PMID: 24843643 PMCID: PMC4019266 DOI: 10.1111/jdi.12050] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/19/2022] Open
Abstract
Diabetic nephropathy is the leading cause of end‐stage renal failure in developed countries. Furthermore, diabetic nephropathy is related to the risk of cardiovascular diseases and an increase in mortality of diabetic patients. Several factors are involved in the development of nephropathy, including glomerular hyperfiltration, oxidative stress, accumulation of advanced glycation end‐products, activation of protein kinase C, acceleration of the polyol pathway and over‐expression of transforming growth factor‐β. Recently, accumulated data have emphasized the critical roles of chronic low‐grade inflammation, ‘microinflammation’, in the pathogenesis of diabetic nephropathy, suggesting that microinflammation is a common mechanism in the development of diabetic vascular complications. Expression of cell adhesion molecules, chemokines and pro‐inflammatory cytokines are increased in the renal tissues of diabetic patients and animals. Deficiency of pro‐inflammatory molecules results in amelioration of renal injuries after induction of diabetes in mice. Plasma and urinary levels of cytokines, chemokines and cell adhesion molecules, are elevated and correlated with albuminuria. Several kinds of drugs that have anti‐inflammatory actions as their pleiotropic effects showed renoprotective effects on diabetic animals. Modulation of the inflammatory process prevents renal insufficiency in diabetic animal models, suggesting that microinflammation is one of the promising therapeutic targets for diabetic nephropathy, as well as for cardiovascular diseases.
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Affiliation(s)
- Kenichi Shikata
- Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan ; Department of Medicine and Clinical Science Okayama University Graduate School of Medicine Dentistry, and Pharmaceutical Science Okayama Japan
| | - Hirofumi Makino
- Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan ; Department of Medicine and Clinical Science Okayama University Graduate School of Medicine Dentistry, and Pharmaceutical Science Okayama Japan
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Sabuncu T, Eren MA, Tabur S, Dag OF, Boduroglu O. High serum concentration of interleukin-18 in diabetic patients with foot ulcers. J Am Podiatr Med Assoc 2014; 104:222-6. [PMID: 24901579 DOI: 10.7547/0003-0538-104.3.222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND It is well known that interleukin-18 (IL-18) plays a key role in the inflammatory process. However, there are limited data on the role IL-18 plays with diabetic foot ulcers, an acute and complex inflammatory situation. Therefore, we aimed to evaluate serum IL-18 levels of diabetic patients with foot ulcers. METHODS Twenty diabetic patients with acute foot ulcers, 21 diabetic patients without a history of foot ulcers, and 21 healthy volunteers were enrolled in our study. Circulating levels of IL-18, and other biochemical markers are parameters of inflammation and were measured in all three groups. RESULTS Diabetic patients both with and without foot ulcers had high IL-18 concentrations (P < 0.001 and P = 0.020, respectively) when compared with the nondiabetic volunteers. Those with foot ulcers had higher levels of IL-18 level (P < 0.001), high-sensitivity C-reactive protein (hsCRP) (P = 0.001), and erythrocyte sedimentation rate (ESR) (P < 0.001) than those without foot ulcers. CONCLUSIONS We found that serum IL-18 concentrations were elevated in diabetic patients with acute diabetic foot ulcers. However, these findings do not indicate whether the IL-18 elevation is a cause or a result of the diabetic foot ulceration. Further studies are needed to show the role of IL-18 in the course of these ulcers.
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Affiliation(s)
- Tevfik Sabuncu
- Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey
| | - Mehmet Ali Eren
- Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey
| | - Suzan Tabur
- Department of Endocrinology, Harran University Faculty of Medicine, Sanliurfa, Turkey
| | - Omer Faruk Dag
- Department of Internal Medicine, Harran University Faculty of Medicine, Sanliurfa, Turkey
| | - Omer Boduroglu
- Department of Internal Medicine, Harran University Faculty of Medicine, Sanliurfa, Turkey
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Omote K, Gohda T, Murakoshi M, Sasaki Y, Kazuno S, Fujimura T, Ishizaka M, Sonoda Y, Tomino Y. Role of the TNF pathway in the progression of diabetic nephropathy in KK-A(y) mice. Am J Physiol Renal Physiol 2014; 306:F1335-47. [PMID: 24647715 DOI: 10.1152/ajprenal.00509.2013] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-α remains unclear. The objectives of the present study were to examine whether TNF-α inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-A(y) mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-α and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-α and TNFR1, in ETN-treated KK-A(y) mice were significantly decreased compared with untreated KK-A(y) mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-α or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-α-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-α-TNFR2 pathway.
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Affiliation(s)
- Keisuke Omote
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Maki Murakoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yu Sasaki
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Saiko Kazuno
- Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Tsutomu Fujimura
- Division of Proteomics and Biomolecular Science, BioMedical Research Center, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masanori Ishizaka
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yuji Sonoda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; and
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Lopes-Virella MF, Baker NL, Hunt KJ, Cleary PA, Klein R, Virella G. Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes Care 2013; 36:2317-23. [PMID: 23514730 PMCID: PMC3714479 DOI: 10.2337/dc12-2521] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria. RESEARCH DESIGN AND METHODS Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest. RESULTS In the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30-50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1. CONCLUSIONS Our study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes.
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Affiliation(s)
- Maria F Lopes-Virella
- Department of Medicine and Laboratory Services, Medical University of South Carolina and Ralph H Johnson VA Medical Center, Charleston, South Carolina, USA.
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Abstract
Chronic and acute renal diseases, irrespective of the initiating cause, have inflammation and immune system activation as a common underlying mechanism. The purpose of this review is to provide a broad overview of immune cells and inflammatory proteins that contribute to the pathogenesis of renal disease, and to discuss some of the physiological changes that occur in the kidney as a result of immune system activation. An overview of common forms of acute and chronic renal disease is provided, followed by a discussion of common therapies that have anti-inflammatory or immunosuppressive effects in the treatment of renal disease.
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Affiliation(s)
- John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Hellemons ME, Kerschbaum J, Bakker SJL, Neuwirt H, Mayer B, Mayer G, de Zeeuw D, Lambers Heerspink HJ, Rudnicki M. Validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes: a systematic review. Diabet Med 2012; 29:567-77. [PMID: 21913962 DOI: 10.1111/j.1464-5491.2011.03437.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Novel biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes have been recently identified. We performed a systematic review to assess the validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes in longitudinal studies. The methodological quality of the studies was scored using Standards for Reporting of Diagnostic Accuracy (STARD) criteria and the independent predictive value of the biomarkers beyond conventional risk factors was scored according to the adjustment for these risk factors. Validity of the biomarkers was determined by summarizing the methodological quality and the adjustment score. We identified 15 studies describing 27 biomarkers. Six studies had sufficient methodological quality. These studies identified 13 valid and significant markers for nephropathy in diabetes: serum interleukin 18, plasma asymmetric dimethylarginine; and urinary ceruloplasmin, immunoglobulin G and transferrin were considered valid markers predicting onset of nephropathy. Plasma asymmetric dimethylarginine, vascular cell adhesion molecule 1, interleukin 6, von Willebrand factor and intercellular cell adhesion molecule 1 were considered valid biomarkers predicting progression of nephropathy. Plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, von Willebrand factor and triglycerides were considered valid markers predicting onset and progression of nephropathy. Several novel biomarkers for prediction of nephropathy in diabetes have been published, which can potentially be applied in clinical practice and research in future. Because of the heterogeneous quality of biomarker studies in this field, a more rigorous evaluation of these biomarkers and validation in larger trials are advocated.
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Affiliation(s)
- M E Hellemons
- Department of Clinical Pharmacology, University Medical Center of Groningen, Groningen, the Netherlands
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Interleukin-1 (IL-1) family of cytokines: role in type 2 diabetes. Clin Chim Acta 2012; 413:1163-70. [PMID: 22521751 DOI: 10.1016/j.cca.2012.03.021] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 03/20/2012] [Accepted: 03/24/2012] [Indexed: 12/17/2022]
Abstract
Cytokines are small cell signaling protein molecules which encompass a large and diverse family. They consist of immunomodulating agents such as interleukins and inteferons. Virtually all nucleated cells, especially endo/epithelial cells and macrophages are potent producers of IL-1, IL-6 and TNF-α. IL-1 family is a group of cytokines which play a central role in the regulation of immune and inflammatory responses. Type 2 diabetes (T2D) has been recognized as an immune mediated disease leading to impaired insulin signaling and selective destruction of insulin producing β-cells in which cytokines play an important role. Disturbance of anti-inflammatory response could be a critical component of the chronic inflammation resulting in T2D. IL-1 family of cytokines has important roles in endocrinology and in the regulation of responses associated with inflammatory stress. The IL-1 family consists of two pro-inflammatory cytokines, IL-1α and IL-1β, and a naturally occurring anti-inflammatory agent, the IL-1 receptor antagonist (IL-1Ra or IL-1RN). This review is an insight into the different types of cytokines belonging to IL-1 family, their modes of action and association with Type 2 diabetes.
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Fujita T, Ogihara N, Kamura Y, Satomura A, Fuke Y, Shimizu C, Wada Y, Matsumoto K. Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications. Acta Diabetol 2012; 49:111-7. [PMID: 20186552 DOI: 10.1007/s00592-010-0178-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 02/01/2010] [Indexed: 11/28/2022]
Abstract
Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.
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Affiliation(s)
- Takayuki Fujita
- Department of Nephrology, Hypertension and Endocrinology, Nihon University School of Medicine, Itabashiku, Tokyo, Japan.
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Luis-Rodríguez D, Martínez-Castelao A, Górriz JL, De-Álvaro F, Navarro-González JF. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. World J Diabetes 2012; 3:7-18. [PMID: 22253941 PMCID: PMC3258536 DOI: 10.4239/wjd.v3.i1.7] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 12/09/2011] [Accepted: 01/09/2012] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication.
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Affiliation(s)
- Desirée Luis-Rodríguez
- Desirée Luis-Rodríguez, Alberto Martínez-Castelao, José Luis Górriz, Fernando de Álvaro, Juan F Navarro-González, Grupo Español para el Estudio de la Nefropatía Diabética (GEENDIAB), Spain
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Abstract
Diabetic nephropathy (DN), the most common cause of end-stage renal disease (ESRD), is increasingly considered an inflammatory process characterized by leukocyte infiltration at every stage of renal involvement. Cytokines act as pleiotropic polypeptides that regulate inflammatory and immune responses, providing important signals in the pathologic and physiologic processes. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Proinflammatory, Th1, Th2, and Th17 cytokines, as well as TGF-beta, all take part in the development and progression of DN. Gene polymorphism of cytokines and their receptors may have functional variations and can be applied to predict the susceptibility and progression to DN. Improved knowledge on recognizing cytokines as significant pathogenic mediators in DN leaves opens the possibility of new potential therapeutic agents for future clinical treatments.
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MESH Headings
- Biomarkers/analysis
- Cytokines/genetics
- Cytokines/immunology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/physiopathology
- Diabetic Nephropathies/complications
- Diabetic Nephropathies/diagnosis
- Diabetic Nephropathies/immunology
- Diabetic Nephropathies/physiopathology
- Disease Progression
- Humans
- Inflammation/complications
- Inflammation/diagnosis
- Inflammation/immunology
- Inflammation/physiopathology
- Kidney/immunology
- Kidney/physiopathology
- Kidney Failure, Chronic/complications
- Kidney Failure, Chronic/diagnosis
- Kidney Failure, Chronic/immunology
- Kidney Failure, Chronic/physiopathology
- Neutrophil Infiltration/immunology
- Polymorphism, Genetic
- Receptors, Cytokine/genetics
- Receptors, Cytokine/immunology
- Th1-Th2 Balance
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Affiliation(s)
- Chia-Chao Wu
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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47
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Lopes-Virella MF, Carter RE, Baker NL, Lachin J, Virella G. High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in Type 1 diabetes. Nephrol Dial Transplant 2011; 27:1416-23. [PMID: 21856760 DOI: 10.1093/ndt/gfr454] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Modified low-density lipoprotein (LDL) immune complexes (IC) have proinflammatory properties and play a role in albuminuria development. METHODS We measured oxidized LDL (oxLDL) and advanced glycation end-product (AGE)-LDL in IC isolated from sera of Type 1 diabetic subjects followed for 14-20 years and studied their association with abnormal albuminuria. Patients with albumin excretion rates (AER)<40 mg/24 h at baseline and follow-up (n=302) were deemed resistant to developing abnormal albuminuria. Patients with AER<40 mg/24 h at baseline whose AER levels progressed to >40 mg/24 h were considered prone to abnormal albuminuria (n=185), those who progress to AER>299 mg/24 h were considered as having macroalbuminuria (n=57). The odds of developing abnormal albuminuria were estimated by logistic regression based on natural log-transformed levels of oxLDL and AGE-LDL in IC and stratified by baseline AER decile. RESULTS OxLDL and AGE-LDL were significantly higher in IC isolated from patients progressing to abnormal albuminuria. In unadjusted conditional logistic analysis, an increase of 1 SD in oxLDL and AGE-LDL levels in IC significantly increased the odds ratio (OR) for development of macroalbuminuria, respectively, by a factor of 2.5 and 1.8 (P<0.001, P=0.008). The increased odds of developing macroalbuminuria remained significant when adjusted for treatment group, diabetes duration, retinopathy, baseline hemoglobin A1c and LDL (OR=2.5 and 1.8, respectively, P<0.01). CONCLUSION Higher levels of oxLDL and AGE-LDL in circulating IC were associated with increased odds to develop abnormal albuminuria.
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Affiliation(s)
- Maria F Lopes-Virella
- Department of Medicine and Laboratory Services, Medical University of South Carolina and Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
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48
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Fujita T, Shimizu C, Fuke Y, Satomura A, Abe M, Kaizu K, Matsumoto K, Soma M. Serum interleukin-18 binding protein increases with behavior different from IL-18 in patients with diabetic nephropathy. Diabetes Res Clin Pract 2011; 92:e66-9. [PMID: 21440322 DOI: 10.1016/j.diabres.2011.02.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 02/17/2011] [Accepted: 02/22/2011] [Indexed: 11/21/2022]
Abstract
We investigated alterations between serum interleukin 18 (IL-18) and IL-18 binding protein (18BP) in T2DM patients. 18 BP began to increase after IL-18 increased and reached a threshold, in which case kidney dysfunction would have developed. These data indicate that 18BP might express glomerular dysfunction more closely than IL-18.
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Affiliation(s)
- Takayuki Fujita
- Department of Nephrology, Hypertension and Endocrinology, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashiku, Tokyo 173-8610, Japan.
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49
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Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011; 7:327-40. [DOI: 10.1038/nrneph.2011.51] [Citation(s) in RCA: 813] [Impact Index Per Article: 58.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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50
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Hall IE, Doshi MD, Poggio ED, Parikh CR. A comparison of alternative serum biomarkers with creatinine for predicting allograft function after kidney transplantation. Transplantation 2011; 91:48-56. [PMID: 21441853 DOI: 10.1097/tp.0b013e3181fc4b3a] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The role of serum cystatin C (Scyc), neutrophil gelatinase-associated lipocalin, and interleukin-18 in predicting early graft function after kidney transplant is poorly defined. METHODS We conducted a multicenter prospective cohort study of deceased-donor kidney transplants. We collected serial blood samples for the first 3 days of transplant and monitored need for dialysis within 1 week and graft function at 3 months after transplant. RESULTS Among 78 recipients with serum biomarker measurements, 26 had delayed graft function (DGF; hemodialysis within 1 week of transplant). Of those not dialyzed, 29 had slow graft function (serum creatinine [Scr] reduction from transplantation to day 7 <70%), and 23 had immediate graft function (IGF; reduction in Scr ≥70%). Scyc levels were statistically different between groups by the first postoperative day (POD), whereas Scr levels were not. Serum neutrophil gelatinase-associated lipocalin and serum interleukin-18 levels were not different between groups. Scyc on the first POD demonstrated good utility for predicting DGF and non-IGF (DGF or slow graft function) with areas under the receiver-operating characteristic curve of 0.83 and 0.85, respectively. Areas under the receiver-operating characteristic curve for predicting DGF and non-IGF using Scr on the first POD were 0.65 and 0.53, respectively. Substituting Scyc for Scr in a clinical algorithm improved its utility for predicting DGF or non-IGF, with adjusted odds ratios of 2.4 and 3.3 for Scyc levels on the first POD. The change in Scyc during the first POD demonstrated a dose-response relationship with 3-month graft function. CONCLUSIONS Scyc outperforms Scr as a predictor of early graft function after deceased-donor kidney transplant.
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Affiliation(s)
- Isaac E Hall
- Section of Nephrology, Department of Medicine, Yale University School of Medicine and the Clinical Epidemiology Research Center, VAMC, New Haven, CT, USA
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