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Pan W, Zhang Q, Gong X, Wu W, Zhou Q. Identification and validation of key extracellular proteins as the potential biomarkers in diabetic nephropathy. Eur J Med Res 2024; 29:517. [PMID: 39456069 PMCID: PMC11515200 DOI: 10.1186/s40001-024-02120-y] [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: 07/12/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
OBJECTIVE Accumulation of extracellular matrix (ECM) proteins in the glomerular mesangial region is a typical hallmark of diabetic nephropathy (DN). However, the molecular mechanism underlying ECM accumulation in the mesangium of DN patients remains unclear. The present study aims to establish a connection between extracellular proteins and DN with the goal of identifying potential biomarkers for this condition. METHODS Differentially expressed genes (DEGs) between DN kidney tissue and healthy kidney tissue were analyzed using the public data GSE166239. Two gene lists encoding extracellular proteins were then utilized to identify extracellular protein-differentially expressed genes (EP-DEGs). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed on these EP-DEGs. A protein-protein interaction (PPI) network was established to identify key EP-DEGs. Furthermore, the diagnostic ability, immune cell infiltration, and clinical relevance of these EP-DEGs were investigated. Immunohistochemistry (IHC) staining of paraffin-embedded renal tissues was performed to validate the accuracy of the bioinformatic results. RESULTS A total of 1204 DEGs were identified, from which 162 EP-DEGs were further characterized by overlapping with extracellular protein gene lists. From the PPI network analysis, five EP-DEGs (e.g., TNF, COL1A1, FN1, MMP9, and TGFB1) were identified as candidate biomarkers. TNF, COL1A1, and MMP9 had a high diagnostic accuracy for DN. Assessment of immune cell infiltration revealed that the expression of TNF was positively associated with resting dendritic cells (DCs) (r = 0.85, P < 0.001) and M1 macrophages (r = 0.62, P < 0.05), whereas negatively associated with regulatory T cells (r = - 0.62, P < 0.05). Nephroseq v5 analysis demonstrated a negative correlation between the estimated glomerular filtration rate (eGFR) and TNF expression (r = - 0.730, P = 0.025). Gene set enrichment analysis (GSEA) revealed significant enrichment of glycosaminoglycan (GAG) degradation in the high-TNF subgroup. IHC staining of renal tissues confirmed significantly elevated TNF-a expression and decreased hyaluronic acid (HA) levels in the DN group compared to controls (both P < 0.05), with a negative correlation observed between TNF-a and HA (r = - 0.691, P = 0.026). CONCLUSION Our findings suggest that TNF may play a pivotal role in the progress of DN by driving ECM accumulation, and this process might involve GAG degradation pathway activation.
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Affiliation(s)
- Wei Pan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Qiankun Zhang
- Department of Nephrology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui Hospital of Zhejiang University, Lishui, 323000, China
| | - Xiaohua Gong
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Wenjun Wu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Qi Zhou
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
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Mahmoud HM, Abdel-Razik ARH, Elrehany MA, Othman EM, Bekhit AA. Modified Citrus Pectin (MCP) Confers a Renoprotective Effect on Early-Stage Nephropathy in Type-2 Diabetic Mice. Chem Biodivers 2024; 21:e202400104. [PMID: 38588017 DOI: 10.1002/cbdv.202400104] [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: 01/15/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/10/2024]
Abstract
Diabetic nephropathy (DN) is a significant global health concern with a high morbidity rate. Accumulating evidence reveals that Galectin-3 (Gal-3), a β-galactoside-binding lectin, is a biomarker in kidney diseases. Our study aimed to assess the advantageous impacts of modified citrus pectin (MCP) as an alternative therapeutic strategy for the initial and ongoing progression of DN in mice with type 2 diabetes mellitus (T2DM). The animal model has been split into four groups: control group, T2DM group (mice received intraperitoneal injections of nicotinamide (NA) and streptozotocin (STZ), T2DM+MCP group (mice received 100 mg/kg/day MCP following T2DM induction), and MCP group (mice received 100 mg/kg/day). After 4 weeks, kidney weight, blood glucose level, serum kidney function tests, histopathological structure alterations, oxidative stress, inflammation, apoptosis, and fibrosis parameters were determined in renal tissues. Our findings demonstrated that MCP treatment reduced blood glucose levels, renal histological damage, and restored kidney weight and kidney function tests. Additionally, MCP reduced malondialdehyde level and restored glutathione level, and catalase activity. MCP demonstrated a notable reduction in inflammatory and apoptosis mediators TNF-α, iNOS, TGF-βRII and caspase-3. Overall, MCP could alleviate renal injury in an experimental model of DN by suppressing renal oxidative stress, inflammation, fibrosis, and apoptosis mediators.
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Affiliation(s)
| | | | - Mahmoud A Elrehany
- Biochemistry Department, Faculty of Pharmacy, Deraya University, New Mina, Egypt
| | - Eman M Othman
- Biochemistry Department, Faculty of Pharmacy, Minia University, 65111, Minia, Egypt E-mail: amany
- Cancer Therapy Research Center, Biochemistry Department -I, Biocenter, University of Wuerzburg, Am Hubland, 97074, Würzburg, Germany
- Bioinformatics Department, Biocenter, University of Wuerzburg, Am Hubland, 97074, Würzburg, Germany
| | - Amany A Bekhit
- Biochemistry Department, Faculty of Pharmacy, Minia University, 65111, Minia, Egypt E-mail: amany
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Oh M, Jung S, Kim YA, Lee GY, Han SN. Dietary vitamin D 3 supplementation enhances splenic NK cell activity in healthy and diabetic male mice. Nutr Res 2024; 127:144-155. [PMID: 38954977 DOI: 10.1016/j.nutres.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 07/04/2024]
Abstract
Type 2 diabetes mellitus negatively affects the immune system, resulting in reduced natural killer (NK) cell activity. Vitamin D has been shown to regulate innate and adaptive immune cells. However, the effects of vitamin D on NK cells remain inconclusive, especially in the context of diabetes. We hypothesized that dietary vitamin D3 supplementation can enhance NK cell activity in diabetic mice. Therefore, we investigated the effects of dietary vitamin D3 on NK cell activity in control and diabetic mice and explored the mechanisms of NK cell activity modulation by vitamin D3. Control (CON) and diabetic mice (db/db) were randomly divided into 2 groups, then fed either a control diet (948 IU vitamin D3/kg diet, vDC) or a diet supplemented with vitamin D3 (9,477 IU vitamin D3/kg diet, vDS) for 8 weeks. Diabetic mice exhibited lower NK cell activity than control mice. The vDS group had significantly higher NK cell activity than the vDC group in both control and diabetic mice. The vDS group had a higher percentage of CD11b single-positive NK cells than the vDC group (CON-vDS 34%; db/db-vDS 30%; CON-vDC 27%; db/db-vDC 22%). The intracellular expression of splenic TGF-β was significantly higher in the db/db group than in the CON group. Overall, vDS group had higher Bcl2 and Tbx21 mRNA expressions than the vDC group. In conclusion, the present study shows that NK cell activity is impaired under diabetic conditions, possibly due to the reduced percentage of mature NK cells. Moreover, NK activity is enhanced by dietary supplementation in both control and diabetic mice that may be associated with changes in the proportion of mature NK cells.
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Affiliation(s)
- Minha Oh
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Sohee Jung
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Yoon-Ah Kim
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Ga Young Lee
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea
| | - Sung Nim Han
- Department of Food and Nutrition, Seoul National University, Seoul, Republic of Korea; Research Institute of Human Ecology, Seoul National University, Seoul, Republic of Korea.
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Nemati M, Hosseinzadeh Z, Nemati F, Koohpeyma F. Improvement effects of transplanting pancreatic islet that previously incubated with biomaterials on the diabetic nephropathy in STZ- diabetic rats. BMC Nephrol 2024; 25:156. [PMID: 38724923 PMCID: PMC11080158 DOI: 10.1186/s12882-024-03572-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 04/05/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Islet transplantation is an effective treatment for diabetes or even its complications. Aim of this study is to investigate efficacy of biomaterial treated islet transplantation on treating diabetic nephropathy. METHODS Male rats were randomly divided into 6 groups; Control, diabetic control, diabetic transplanted with untreated islets, with platelet rich plasma treated islets, with pancreatic islets homogenate treated islets, or with these biomaterials combination treated islets. Islets cultured with biomaterials and transplanted to diabetic rats. After 60 days, biochemical, oxidative stress, and stereological parameters were assessed. RESULTS Serum albumin and BUN concentration, decreased and increased respectively, Oxidative stress of kidney impaired, kidney weight, volume of kidney, cortex, medulla, glomerulus, proximal and distal tubules, collecting ducts, vessels, inflammatory, necrotic and fibrotic tissue in diabetic group increased compared to control group (p < 0.001). In treated groups, especially pancreatic islets homogenate treated islets transplanting animals, there was significant changes in kidney weight, and volume of kidney, proximal and distal tubules, Henle's loop and collecting ducts compared with diabetic group (p = 0.013 to p < 0.001). Combination treated islets animals showed significant increase in vessel volume compared to diabetic group (p < 0.001). Necrotic and fibrotic tissue significantly decreased in islets treated than untreated islet animals, it was higher in pancreatic islets homogenate, and combination treated islets groups (p = 0.001). CONCLUSIONS Biomaterials treated islets transplanting could improve diabetic nephropathy. Improvement of oxidative stress followed by controlling glucose level, and effects of growth factors presenting in biomaterials can be considered as capable underlying mechanism of ameliorating inflammatory, necrotic and fibrotic tissue volume.
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Affiliation(s)
- Marzieh Nemati
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Zahra Hosseinzadeh
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Nemati
- School of Dentistry, Shiraz University of Medical Science, Shiraz, Iran
| | - Farhad Koohpeyma
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Klen J, Dolžan V. SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation. Pharmaceutics 2023; 15:1995. [PMID: 37514181 PMCID: PMC10386344 DOI: 10.3390/pharmaceutics15071995] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/30/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels.
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Affiliation(s)
- Jasna Klen
- Division of Surgery, Department of Abdominal Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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Rai B, Pande A, Tiwari S. TRAIL and EGFR Pathways Targeting microRNAs are Predominantly Regulated in Human Diabetic Nephropathy. Microrna 2023; 12:143-155. [PMID: 37098997 DOI: 10.2174/2211536612666230407093841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/02/2023] [Accepted: 02/01/2023] [Indexed: 04/27/2023]
Abstract
BACKGROUND Unbiased microRNA profiling of renal tissue and urinary extracellular vesicles (uEVs) from diabetic nephropathy (DN) subjects may unravel novel targets with diagnostic and therapeutic potential. Here we used the miRNA profile of uEVs and renal biopsies from DN subjects available on the GEO database. METHODS The miR expression profiles of kidney tissue (GSE51674) and urinary exosomes (GSE48318) from DN and control subjects were obtained by GEO2R tools from Gene Expression Omnibus (GEO) databases. Differentially expressed miRNAs in DN samples, relative to controls, were identified using a bioinformatic pipeline. Targets of miRs commonly regulated in both sample types were predicted by miRWalk, followed by functional gene enrichment analysis. Gene targets were identified by MiRTarBase, TargetScan and MiRDB. RESULTS Eight miRs, including let-7c, miR-10a, miR-10b and miR-181c, were significantly regulated in kidney tissue and uEVs in DN subjects versus controls. The top 10 significant pathways targeted by these miRs included TRAIL, EGFR, Proteoglycan syndecan, VEGF and Integrin Pathway. Gene target analysis by miRwalk upon validation using ShinyGO 70 targets with significant miRNA-mRNA interaction. CONCLUSION In silico analysis showed that miRs targeting TRAIL and EGFR signaling are predominately regulated in uEVs and renal tissue of DN subjects. After wet-lab validation, the identified miRstarget pairs may be explored for their diagnostic and/or therapeutic potential in diabetic nephropathy.
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Affiliation(s)
- Bhuvnesh Rai
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Akshara Pande
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Khalifa AS, Elshebiny A, Eed EM, Elhelbawy MG, Rizk SK. Genetic variations of tumor necrosis factor-α and prostaglandin-endoperoxide synthase 2 genes among Egyptian patients with type 2 diabetes mellitus and diabetic nephropathy. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Teuma L, Eshwaran R, Tawokam Fongang U, Wieland J, Shao F, Lagana ML, Wang Y, Agaci A, Hammes HP, Feng Y. Glucosamine inhibits extracellular matrix accumulation in experimental diabetic nephropathy. Front Nutr 2022; 9:1048305. [PMID: 36532524 PMCID: PMC9751334 DOI: 10.3389/fnut.2022.1048305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2023] Open
Abstract
INTRODUCTION Glucosamine, the intermediate metabolite of the hexosamine biosynthesis pathway (HBP), is widely used as a supplementary drug in patients with osteoarthritis. However, its consequences in such patients concomitantly suffering from diabetic nephropathy is unknown. METHODS The aim of the study was to investigate the effect of exogenous administration of glucosamine in the diabetic kidney. A mouse model of streptozotocin-induced diabetic nephropathy in vivo and cultured endothelial cells in vitro were used in the study. The mice were treated with glucosamine for 6 months. Renal function was evaluated by metabolic cage, and histology of the kidney was estimated by periodic acid-schiff (PAS) staining. The expression of related genes was assessed by real-time PCR, immunofluorescence staining, immunoblotting and ELISA. RESULTS There was no significant difference in urinary albumin secretion, relative kidney weight, or creatinine clearance between the groups treated with glucosamine and controls. Assessment of the kidney demonstrated reduction in mesangial expansion and fibronectin expression in the diabetic glomeruli treated with glucosamine. Glucosamine treatment significantly decreased α-smooth muscle actin (α-SMA) protein expression in both diabetic and control kidneys, whereas the expression of other fibrosis-related genes and inflammatory factors was unaltered. Moreover, α-SMA colocalized with the endothelial marker CD31 in the diabetic and control kidneys, and glucosamine reduced α-SMA+ ECs in the diabetic glomeruli. In addition, glucosamine suppressed α-SMA expression in endothelial cells treated with or without high glucose. DISCUSSION In summary, this is the first report to show that glucosamine reduces mesangial expansion and inhibits endothelial-mesenchymal transition in diabetic nephropathy. The underlying mechanisms need to be further investigated.
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Affiliation(s)
- Loic Teuma
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Rachana Eshwaran
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Ulrich Tawokam Fongang
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Johanna Wieland
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Feng Shao
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Maria Luisa Lagana
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Yixin Wang
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Ane Agaci
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
| | - Hans-Peter Hammes
- 5th Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yuxi Feng
- Experimental Pharmacology Mannheim, Medical Faculty Mannheim, European Center for Angioscience (ECAS), Heidelberg University, Mannheim, Germany
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Role of NOD-Like Receptors in a Miniature Pig Model of Diabetic Renal Injuries. Mediators Inflamm 2022; 2022:5515305. [PMID: 35399795 PMCID: PMC8986423 DOI: 10.1155/2022/5515305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 02/12/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022] Open
Abstract
Activation of NOD-like receptor (NLR) signaling pathway can promote downstream cytokine and proinflammatory cytokines release, and inflammation induced by excess nutrients leads to renal metabolic injury. How the NLRs influence metabolic progress and then lead to the renal injury remains poorly investigated. Compared with rodents, minipigs are more similar to humans and are more ideal animal models for human disease research. In this study, we established a diabetic minipig model through a high-sugar and high-fat diet combined with streptozotocin (STZ) injection. Blood biological markers and renal pathological markers, expression of NLRP subfamily members (NLRP1 and NLRP3) and their downstream cytokines (precursors of IL-1β and IL-18 and mature forms of IL-1β and IL-18), expression of NLRC subfamily members (NLRC1, NLRC2, and NLRC5) and their downstream nuclear factor-κB (NF-κB) signaling pathway molecules (IKKβ, IκBα, and NF-κB p65), and inflammatory cytokines (TNF-α and interleukin-6 (IL-6)) were systematically evaluated. The expression of NLRP3 and its downstream cytokine signaling molecules, the precursors of IL-1β and IL-18, and the mature forms of IL-1β and IL-18 was significantly upregulated. The expression levels of NLRC1, NLRC2, and NLRC5 and activation of the downstream NF-κB pathway molecules phospho-IKKβ, phospho-IκBα, NF-κB p65, and phospho-NF-κB p65 were significantly increased. The TNF-α and IL-6 levels were significantly increased in diabetic pig kidneys. The TGF-β/Smad signaling molecules, TGF-β and P-SMAD2/3, were also increased. These results suggested that the metabolic inflammation activated by NLRs might play an important role in diabetic renal injuries.
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Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1497449. [PMID: 34307650 PMCID: PMC8285185 DOI: 10.1155/2021/1497449] [Citation(s) in RCA: 471] [Impact Index Per Article: 117.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting A1c < 7%, and <130/80 mmHg. Regression of albuminuria remains an important therapeutic goal. However, there are problems in diagnosis and treatment of nonproteinuric DN (NP-DN), which does not follow the classic pattern of DN. In fact, the prevalence of DN continues to increase, and additional therapy is needed to prevent or ameliorate the condition. In addition to conventional therapies, vitamin D receptor activators, incretin-related drugs, and therapies that target inflammation may also be promising for the prevention of DN progression. This review focuses on the role of inflammation and oxidative stress in the pathogenesis of DN, approaches to diagnosis in classic and NP-DN, and current and emerging therapeutic interventions.
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Md Dom ZI, Pipino C, Krolewski B, O'Neil K, Satake E, Krolewski AS. Effect of TNFα stimulation on expression of kidney risk inflammatory proteins in human umbilical vein endothelial cells cultured in hyperglycemia. Sci Rep 2021; 11:11133. [PMID: 34045516 PMCID: PMC8160214 DOI: 10.1038/s41598-021-90496-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/26/2021] [Indexed: 12/11/2022] Open
Abstract
We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFα. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFα in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFα-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFα. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes.
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Affiliation(s)
- Zaipul I Md Dom
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Caterina Pipino
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA.,Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Bozena Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Eiichiro Satake
- Research Division, Joslin Diabetes Center, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Andrzej S Krolewski
- Research Division, Joslin Diabetes Center, Boston, MA, USA. .,Department of Medicine, Harvard Medical School, Boston, MA, USA. .,Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA.
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Blaine J, Dylewski J. Regulation of the Actin Cytoskeleton in Podocytes. Cells 2020; 9:cells9071700. [PMID: 32708597 PMCID: PMC7408282 DOI: 10.3390/cells9071700] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022] Open
Abstract
Podocytes are an integral part of the glomerular filtration barrier, a structure that prevents filtration of large proteins and macromolecules into the urine. Podocyte function is dependent on actin cytoskeleton regulation within the foot processes, structures that link podocytes to the glomerular basement membrane. Actin cytoskeleton dynamics in podocyte foot processes are complex and regulated by multiple proteins and other factors. There are two key signal integration and structural hubs within foot processes that regulate the actin cytoskeleton: the slit diaphragm and focal adhesions. Both modulate actin filament extension as well as foot process mobility. No matter what the initial cause, the final common pathway of podocyte damage is dysregulation of the actin cytoskeleton leading to foot process retraction and proteinuria. Disruption of the actin cytoskeleton can be due to acquired causes or to genetic mutations in key actin regulatory and signaling proteins. Here, we describe the major structural and signaling components that regulate the actin cytoskeleton in podocytes as well as acquired and genetic causes of actin dysregulation.
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Affiliation(s)
- Judith Blaine
- Renal Division, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - James Dylewski
- Renal Division, University of Colorado Anschutz Medical Campus and Denver Health Medical Center, Aurora, CO 80045, USA
- Correspondence: ; Tel.: +303-724-4841
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Han DC, Ziyadeh FN. Favorable Treatment Outcome with Neutralizing anti Transforming Growth Factor I:} Antibodies in Experimental Diabetic Kidney Disease. Perit Dial Int 2020. [DOI: 10.1177/089686089901902s39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Dong Cheol Han
- Renal-Electrolyte and Hypertension Division, and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, U.S.A
| | - Fuad N. Ziyadeh
- Renal-Electrolyte and Hypertension Division, and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, U.S.A
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Zhang L, Wen Z, Han L, Zheng Y, Wei Y, Wang X, Wang Q, Fang X, Zhao L, Tong X. Research Progress on the Pathological Mechanisms of Podocytes in Diabetic Nephropathy. J Diabetes Res 2020; 2020:7504798. [PMID: 32695831 PMCID: PMC7368941 DOI: 10.1155/2020/7504798] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/03/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic nephropathy (DN) is not only an important microvascular complication of diabetes but also the main cause of end-stage renal disease. Studies have shown that the occurrence and development of DN are closely related to morphological and functional changes in podocytes. A series of morphological changes after podocyte injury in DN mainly include podocyte hypertrophy, podocyte epithelial-mesenchymal transdifferentiation, podocyte detachment, and podocyte apoptosis; functional changes mainly involve podocyte autophagy. More and more studies have shown that multiple signaling pathways play important roles in the progression of podocyte injury in DN. Here, we review research progress on the pathological mechanism of morphological and functional changes in podocytes associated with DN, to provide a new target for delaying the occurrence and development of this disorder.
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Affiliation(s)
- Lili Zhang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Zhige Wen
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Lin Han
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Yujiao Zheng
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Yu Wei
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Xinmiao Wang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing Wang
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Xinyi Fang
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Linhua Zhao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiaolin Tong
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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15
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Yaribeygi H, Maleki M, Sathyapalan T, Sahebkar A. The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms. Life Sci 2019; 237:116950. [PMID: 31605709 DOI: 10.1016/j.lfs.2019.116950] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, UK
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Li J, Wu B, Hu H, Fang X, Liu Z, Wu S. GdCl 3 attenuates the glomerular sclerosis of streptozotocin (STZ) induced diabetic rats via inhibiting TGF-β/Smads signal pathway. J Pharmacol Sci 2019; 142:41-49. [PMID: 31831259 DOI: 10.1016/j.jphs.2019.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/25/2019] [Accepted: 06/19/2019] [Indexed: 01/05/2023] Open
Abstract
Diabetic nephropathy (DN) is the most serious end-stage renal disease which characterized by renal glomerular sclerosis including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, mesangial expansion and renal fibrosis. TGF-β/Smads signal pathway plays a crucial role in the development of renal fibrosis. In this study, we found that GdCl3 which was an agonist of Calcium-sensing receptor (CaSR) could repress the activation of TGF-β/Smads signal pathway induced by TGF-β1 or high glucose and then alleviated the accumulation of extracellular matrix (ECM) in mesangial cells and the kidney of type1 diabetic rats. Further study indicated that GdCl3 could induce the binding of CaSR and TβR II and then both of these two receptors translocated from cell membrane to cytoplasm, in this case, TβR II on the cell membrane was decreased and then desensitized to the stimulation of its ligand TGF-β1, so that the activation of its downstream factors such as Smad2 and Smad3 were blocked, finally, ECM expression in mesangial cells were inhibited. We concluded that GdCl3 could alleviate the accumulation of ECM in mesangial cells via antagonizing TGF-β/Smads signal pathway in diabetes mellitus.
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Affiliation(s)
- Jialin Li
- College of Pharmacy, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Bing Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Haibo Hu
- College of Pharmacy, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiansong Fang
- The First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Zhiping Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China.
| | - Suzhen Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China.
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17
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Yaribeygi H, Atkin SL, Sahebkar A. Interleukin-18 and diabetic nephropathy: A review. J Cell Physiol 2019; 234:5674-5682. [PMID: 30417374 DOI: 10.1002/jcp.27427] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/21/2018] [Indexed: 12/17/2022]
Abstract
The inflammatory response has an important role in the pathophysiology of diabetic nephropathy that is contributed to by inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α, and macrophage chemotactic protein-1; however, the role of IL-18 seems to be more specific than other cytokines in the inflammatory process. IL-18 is expressed in renal tissue and is upregulated by several stimuli including hyperglycemia. The expression/urinary level of IL-18 is positively correlated with the progression of diabetic nephropathy and the urinary albumin excretion rate. In this review, we have focused on the molecular pathways modulating the relationship between IL-18 and diabetic nephropathy.
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Affiliation(s)
- Habib Yaribeygi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Quintans JSS, Shanmugam S, Heimfarth L, Araújo AAS, Almeida JRGDS, Picot L, Quintans-Júnior LJ. Monoterpenes modulating cytokines - A review. Food Chem Toxicol 2018; 123:233-257. [PMID: 30389585 DOI: 10.1016/j.fct.2018.10.058] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/11/2018] [Accepted: 10/24/2018] [Indexed: 12/15/2022]
Abstract
Inflammatory response can be driven by cytokine production and is a pivotal target in the management of inflammatory diseases. Monoterpenes have shown that promising profile as agents which reduce the inflammatory process and also modulate the key chemical mediators of inflammation, such as pro and anti-inflammatory cytokines. The main interest focused on monoterpenes were to develop the analgesic and anti-inflammatory drugs. In this review, we summarized current knowledge on monoterpenes that produce anti-inflammatory effects by modulating the release of cytokines, as well as suggesting that which monoterpenoid molecules may be most effective in the treatment of inflammatory disease. Several different inflammatory markers were evaluated as a target of monoterpenes. The proinflammatory and anti-inflammatory cytokines were found TNF-α, IL-1β, IL-2, IL-5, IL-4, IL-6, IL-8, IL-10, IL-12 IL-13, IL-17A, IFNγ, TGF-β1 and IFN-γ. Our review found evidence that NF-κB and MAPK signaling are important pathways for the anti-inflammatory action of monoterpenes. We found 24 monoterpenes that modulate the production of cytokines, which appears to be the major pharmacological mechanism these compounds possess in relation to the attenuation of inflammatory response. Despite the compelling evidence supporting the anti-inflammatory effect of monoterpenes, further studies are necessary to fully explore their potential as anti-inflammatory compounds.
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Affiliation(s)
- Jullyana S S Quintans
- Laboratory of Neuroscience and Pharmacological Assays, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | - Saravanan Shanmugam
- Laboratory of Neuroscience and Pharmacological Assays, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | - Luana Heimfarth
- Laboratory of Neuroscience and Pharmacological Assays, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | | | - Jackson R G da S Almeida
- Center for Studies and Research of Medicinal Plants (NEPLAME), Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil
| | - Laurent Picot
- UMRi CNRS 7266 LIENSs, University of La Rochelle, 17042, La Rochelle, France
| | - Lucindo J Quintans-Júnior
- Laboratory of Neuroscience and Pharmacological Assays, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil.
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19
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Fernández-Juárez G, Villacorta Perez J, Luño Fernández JL, Martinez-Martinez E, Cachofeiro V, Barrio Lucia V, Tato Ribera AM, Mendez Abreu A, Cordon A, Oliva Dominguez JA, Praga Terente M. High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy. Nephrology (Carlton) 2017; 22:354-360. [PMID: 27003829 DOI: 10.1111/nep.12781] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 02/25/2016] [Accepted: 03/15/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria. METHODS Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death. RESULTS The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers. CONCLUSIONS Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers.
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20
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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: 197] [Impact Index Per Article: 24.6] [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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21
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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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22
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Abstract
Kidney disease is a serious development in diabetes mellitus and poses an increasing clinical problem. Despite increasing incidence and prevalence of diabetic kidney disease, there have been no new therapies for this condition in the last 20 years. Mounting evidence supports a biological role for C-peptide, and findings from multiple studies now suggest that C-peptide may beneficially affect the disturbed metabolic and pathophysiological pathways leading to the development of diabetic nephropathy. Studies of C-peptide in animal models and in humans with type 1 diabetes all suggest a renoprotective effect for this peptide. In diabetic rodents, C-peptide reduces glomerular hyperfiltration and albuminuria. Cohort studies of diabetic patients with combined islet and kidney transplants suggest that maintained C-peptide secretion is protective of renal graft function. Further, in short-term studies of patients with type 1 diabetes, administration of C-peptide is also associated with a lowered hyperfiltration rate and reduced microalbuminuria. Thus, the available information suggests that type 1 diabetes should be regarded as a dual hormone deficiency disease and that clinical trials of C-peptide in diabetic nephropathy are both justified and urgently required.
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Affiliation(s)
- N J Brunskill
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
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23
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Sadar S, Kaspate D, Vyawahare N. Protective effect of L-glutamine against diabetes-induced nephropathy in experimental animal: Role of KIM-1, NGAL, TGF-β1, and collagen-1. Ren Fail 2016; 38:1483-1495. [PMID: 27756197 DOI: 10.1080/0886022x.2016.1227918] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Diabetic nephropathy is a serious microvascular complication and one of the main causes of end-stage renal disease. L-Glutamine (LG) is naturally occurring amino acids with antidiabetic and antioxidant potential. The aim of present investigation was to evaluate the potential of LG against streptozotocin (STZ)-induced diabetic nephropathy (DN) in laboratory rats. DN was induced in male Wistar rats (200-220 g) by intraperitoneal administration of STZ (55 mg/kg). Animals were treated orally with either distilled water (10 mg/kg) or LG (250, 500, and 1000 mg/kg) or Sitagliptin (5 mg/kg). Various biochemical, molecular, and histological (hematoxylin-eosin and Masson's trichrome stain) parameters were assessed. Administration of LG (500 and 1000 mg/kg) significantly inhibited (p < .05) STZ-induced alterations in serum and urine biochemistry (urine creatinine, uric acid, albumin, and BUN). It also significantly increased creatinine clearance rate. STZ induced increase in renal oxidonitrosative stress was significantly decreased (p < .05) by LG (500 and 1000 mg/kg) treatment. Upregulated renal KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expression after STZ administration was significantly inhibited (p < .05) by LG (500 and 1000 mg/kg) treatment. Correlation analysis also revealed that antidiabetic potential of LG attenuates STZ-induced elevated renal KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expression. Histopathological alteration induced by STZ in renal tissue was ameliorated by LG treatment. In conclusion, results of present investigation suggest that treatment with LG ameliorated STZ-induced DN via the inhibition of oxidonitrosative stress as well as downregulation of KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expressions.
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Affiliation(s)
- Smeeta Sadar
- a Padmashree Dr D. Y. Patil College of Pharmacy , Akurdi , Pune , Maharashtra , India
| | - Dipti Kaspate
- b Cognizant Technology Solution , Hinjewadi, Pune , Maharashtra , India
| | - Neeraj Vyawahare
- a Padmashree Dr D. Y. Patil College of Pharmacy , Akurdi , Pune , Maharashtra , India
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24
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Takashima Y, Keino-Masu K, Yashiro H, Hara S, Suzuki T, van Kuppevelt TH, Masu M, Nagata M. Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling. Am J Physiol Renal Physiol 2016; 310:F395-408. [PMID: 26764203 DOI: 10.1152/ajprenal.00445.2015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 12/27/2015] [Indexed: 12/11/2022] Open
Abstract
Glomerular integrity and functions are maintained by growth factor signaling. Heparan sulfate, the major component of glomerular extracellular matrixes, modulates growth factor signaling, but its roles in glomerular homeostasis are unknown. We investigated the roles of heparan sulfate 6-O-endosulfatases, sulfatase (Sulf)1 and Sulf2, in glomerular homeostasis. Both Sulf1 and Sulf2 were expressed in the glomeruli of wild-type (WT) mice. Sulf1 and Sulf2 double-knockout (DKO) mice showed glomerular hypercellularity, matrix accumulation, mesangiolysis, and glomerular basement membrane irregularity. Platelet-derived growth factor (PDGF)-B and PDGF receptor-β were upregulated in Sulf1 and Sulf2 DKO mice compared with WT mice. Glomeruli from Sulf1 and Sulf2 DKO mice in vitro stimulated by either PDGF-B, VEGF, or transforming growth factor-β similarly showed reduction of phospho-Akt, phospho-Erk1/2, and phospho-Smad2/3, respectively. Since glomerular lesions in Sulf1 and Sulf2 DKO mice were reminiscent of diabetic nephropathy, we examined the effects of Sulf1 and Sulf2 gene disruption in streptozotocin-induced diabetes. Diabetic WT mice showed an upregulation of glomerular Sulf1 and Sulf2 mRNA by in situ hybridization. Diabetic DKO mice showed significant increases in albuminuria and serum creatinine and an acceleration of glomerular pathology without glomerular hypertrophy; those were associated with a reduction of glomerular phospho-Akt. In conclusion, Sulf1 and Sulf2 play indispensable roles to maintain glomerular integrity and protective roles in diabetic nephropathy, probably by growth factor modulation.
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Affiliation(s)
- Yasutoshi Takashima
- Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Kazuko Keino-Masu
- Molecular Neurobiology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and
| | - Hiroshi Yashiro
- Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Satoshi Hara
- Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Tomo Suzuki
- Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Toin H van Kuppevelt
- Department of Matrix Biochemistry, Nijmegen Center for Molecular Life Sciences, Radbout University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Masayuki Masu
- Molecular Neurobiology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and
| | - Michio Nagata
- Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
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25
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Gallic acid ameliorates renal functions by inhibiting the activation of p38 MAPK in experimentally induced type 2 diabetic rats and cultured rat proximal tubular epithelial cells. Chem Biol Interact 2015; 240:292-303. [PMID: 26341651 DOI: 10.1016/j.cbi.2015.08.026] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/14/2015] [Accepted: 08/31/2015] [Indexed: 12/26/2022]
Abstract
Diabetic nephropathy (DN) is one of the leading causes of morbidity and mortality in diabetic patients that accounts for about 40% of deaths in type 2 diabetes. p38 mitogen activated protein kinase (p38 MAPK), a serine-threonine kinase, plays an important role in tissue inflammation and is known to be activated under conditions of oxidative stress and hyperglycemia. The role of p38 MAPK has been demonstrated in DN, and its inhibition has been suggested as an alternative approach in the treatment of DN. In the present study, we investigated the nephroprotective effects of an anti-inflammatory phenolic compound, gallic acid (GA, 3,4,5-trihydroxybenzoic acid), in high fat diet/streptozotocin (HFD/STZ) induce type 2 diabetic wistar albino rats. GA (25 mg/kgbw and 50 mg/kgbw, p.o.) treatment for 16 weeks post induction of diabetes led to a significant reduction in the levels of blood glucose, HbA1c, serum creatinine, blood urea nitrogen and proteinuria as well as a significant reduction in the levels of creatinine clearance. GA significantly inhibited the renal p38 MAPK and nuclear factor kappa B (N-κB) activation as well as significantly reduced the levels of renal transforming growth factor beta (TGF-β) and fibronectin. Treatment with GA resulted in a significant reduction in the serum levels of proinflammatory cytokines viz. interleukin 1 beta (IL-1β), IL-6 and tumor necrosis factor alpha (TNF-α). Moreover, GA significantly lowered renal pathology and attenuated renal oxidative stress. In cultured rat NRK 52E proximal tubular epithelial cells, GA treatment inhibited high glucose induced activation of p38 MAPK and NF-κB as well as suppressed proinflammatory cytokine synthesis. The results of the present study provide in vivo and in vitro evidences that the p38 MAPK pathway plays an important role in the pathogenesis of DN, and GA attenuates the p38 MAPK-mediated renal dysfunction in HFD/STZ induced type 2 diabetic rats.
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26
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Awad AS, You H, Gao T, Cooper TK, Nedospasov SA, Vacher J, Wilkinson PF, Farrell FX, Brian Reeves W. Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury. Kidney Int 2015; 88:722-33. [PMID: 26061548 PMCID: PMC4589442 DOI: 10.1038/ki.2015.162] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 03/24/2015] [Accepted: 04/09/2015] [Indexed: 01/15/2023]
Abstract
Monocyte/macrophage recruitment correlates strongly with the progression of diabetic nephropathy. Tumor necrosis factor-alpha (TNF-α) is produced by monocytes/macrophages but the direct role of TNF-α and/or macrophage-derived TNF-α in the progression of diabetic nephropathy remains unclear. Here we tested whether inhibition of TNF-α confers kidney protection in diabetic nephropathy via a macrophage-derived TNF-α dependent pathway. Compared to vehicle-treated mice, blockade of TNF-α with a murine anti-TNF-α antibody conferred kidney protection in Ins2Akita mice as indicated by reductions in albuminuria, plasma creatinine, histopathologic changes, kidney macrophage recruitment and plasma inflammatory cytokine levels at 18 weeks of age. To assess the direct role of macrophage-derived TNF-α in diabetic nephropathy, we generated macrophage specific TNF-α deficient mice (CD11bCre/TNF-αFlox/Flox). Conditional ablation of TNF-α in macrophages significantly reduced albuminuria, the increase in plasma creatinine and BUN, histopathologic changes and kidney macrophage recruitment compared to diabetic TNF-αFlox/Flox control mice after 12 weeks of streptozotocin-induced diabetes. Thus, production of TNF-α by macrophages plays a major role in diabetic renal injury. Hence, blocking TNF-α could be a novel therapeutic approach for treatment of diabetic nephropathy.
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Affiliation(s)
- Alaa S Awad
- Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Hanning You
- Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ting Gao
- Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Timothy K Cooper
- Department of Comparative Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Sergei A Nedospasov
- Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia
| | - Jean Vacher
- Clinical Research Institute of Montreal, Départment de Médecine, Université de Montréal, Montreal, Quebec, Canada
| | - Patrick F Wilkinson
- Department of Immunology Research, Janssen R&D, Spring House, Pennsylvania, USA
| | - Francis X Farrell
- Department of Immunology Research, Janssen R&D, Spring House, Pennsylvania, USA
| | - W Brian Reeves
- Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
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Chung CH, Fan J, Lee EY, Kang JS, Lee SJ, Pyagay PE, Khoury CC, Yeo TK, Khayat MF, Wang A, Chen S. Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy. NEPHRON EXTRA 2015; 5:1-18. [PMID: 25852733 PMCID: PMC4369122 DOI: 10.1159/000369576] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background/Aims Tumor necrosis factor (TNF)-α is believed to play a role in diabetic kidney disease. This study explores the specific effects of TNF-α with regard to nephropathy-relevant parameters in the podocyte. Methods Cultured mouse podocytes were treated with recombinant TNF-α and assayed for production of monocyte chemoattractant protein-1 (MCP-1) by enzyme-linked immunosorbent assay (ELISA). TNF-α signaling of MCP-1 was elucidated by antibodies against TNF receptor (TNFR) 1 or TNFR2 or inhibitors of nuclear factor-kappaB (NF-κB), phosphatidylinositol 3-kinase (PI3K) or Akt. In vivo studies were done on male db/m and type 2 diabetic db/db mice. Levels of TNF-α and MCP-1 were measured by RT-qPCR and ELISA in the urine, kidney and plasma of the two cohorts and correlated with albuminuria. Results Podocytes treated with TNF-α showed a robust increase (∼900%) in the secretion of MCP-1, induced in a dose- and time-dependent manner. Signaling of MCP-1 expression occurred through TNFR2, which was inducible by TNF-α ligand, but did not depend on TNFR1. TNF-α then proceeded via the NF-κB and the PI3K/Akt systems, based on the effectiveness of the inhibitors of those pathways. For in vivo relevance to diabetic kidney disease, TNF-α and MCP-1 levels were found to be elevated in the urine of db/db mice but not in the plasma. Conclusion TNF-α potently stimulates podocytes to produce MCP-1, utilizing the TNFR2 receptor and the NF-κB and PI3K/Akt pathways. Both TNF-α and MCP-1 levels were increased in the urine of diabetic db/db mice, correlating with the severity of diabetic albuminuria.
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Affiliation(s)
- Choon Hee Chung
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA ; Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jingyi Fan
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA ; Pediatric Department, Wuhan University School of Medicine, Zhongnan Affiliated Hospital, Wuhan, P.R. China
| | - Eun Young Lee
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA ; Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jeong Suk Kang
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Seung Joo Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Petr E Pyagay
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA
| | - Charbel C Khoury
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA
| | - Tet-Kin Yeo
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA
| | - Mark F Khayat
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA
| | - Amy Wang
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA
| | - Sheldon Chen
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Ill., USA ; Section of Nephrology, MD Anderson Cancer Center, Houston, Tex., USA
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Ahad A, Mujeeb M, Ahsan H, Siddiqui WA. Prophylactic effect of baicalein against renal dysfunction in type 2 diabetic rats. Biochimie 2014; 106:101-10. [DOI: 10.1016/j.biochi.2014.08.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 08/12/2014] [Indexed: 12/20/2022]
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Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules 2014; 19:12727-59. [PMID: 25140450 PMCID: PMC6271622 DOI: 10.3390/molecules190812727] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 08/06/2014] [Accepted: 08/12/2014] [Indexed: 12/16/2022] Open
Abstract
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis.
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Affiliation(s)
- Bo-hyun Choi
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420-743, Korea.
| | - Kyung-Shin Kang
- Daewon Foreign Language High School, Kwangjin-gu, Seoul 143-713, Korea.
| | - Mi-Kyoung Kwak
- College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420-743, Korea.
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García-García PM, Getino-Melián MA, Domínguez-Pimentel V, Navarro-González JF. Inflammation in diabetic kidney disease. World J Diabetes 2014; 5:431-443. [PMID: 25126391 PMCID: PMC4127580 DOI: 10.4239/wjd.v5.i4.431] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 02/24/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.
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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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Lampropoulou IT, Stangou M, Papagianni A, Didangelos T, Iliadis F, Efstratiadis G. TNF-α and microalbuminuria in patients with type 2 diabetes mellitus. J Diabetes Res 2014; 2014:394206. [PMID: 25587544 PMCID: PMC4284977 DOI: 10.1155/2014/394206] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Revised: 09/11/2014] [Accepted: 09/19/2014] [Indexed: 01/15/2023] Open
Abstract
AIM Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). PATIENTS-METHODS Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA. RESULTS Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels. CONCLUSIONS In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria.
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Affiliation(s)
- I.-Th. Lampropoulou
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
| | - M. Stangou
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
| | - A. Papagianni
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
- *A. Papagianni:
| | - T. Didangelos
- 1st Propedeutic Department of Internal Medicine, Diabetes Center, “AHEPA” General Hospital, Aristotle University of Thessaloniki, 546 36 Thessaloniki, Greece
| | - F. Iliadis
- 1st Propedeutic Department of Internal Medicine, Diabetes Center, “AHEPA” General Hospital, Aristotle University of Thessaloniki, 546 36 Thessaloniki, Greece
| | - G. Efstratiadis
- Department of Nephrology, “Hippokratio” General Hospital, Aristotle University of Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
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Siddiqui S, Ahsan H, Khan MR, Siddiqui WA. Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by modulation in TGF-β expression. Toxicol Appl Pharmacol 2013; 273:314-24. [DOI: 10.1016/j.taap.2013.09.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 09/04/2013] [Accepted: 09/06/2013] [Indexed: 10/26/2022]
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Gupta S, Gambhir JK, Kalra O, Gautam A, Shukla K, Mehndiratta M, Agarwal S, Shukla R. Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population. J Diabetes Complications 2013; 27:548-52. [PMID: 24012111 DOI: 10.1016/j.jdiacomp.2013.07.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 07/11/2013] [Accepted: 07/21/2013] [Indexed: 12/23/2022]
Abstract
Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide. It results from diverse etiologies, diabetes being a frontrunner amongst them. Type 2 diabetes mellitus (DM) is being increasingly recognized as a proinflammatory state with increased oxidative stress which enormously increases the risk of micro and macro vascular diseases. This study was planned to explore the possible association between tumor necrosis factor-alpha (TNF-α), urinary monocyte chemoattractant protein-1 (uMCP-1), high-sensitivity C-reactive protein (hsCRP) and parameters of oxidative stress in patients with Type 2 diabetes mellitus (DM) and diabetic chronic kidney disease (DM-CKD). Fifty patients each were recruited in DM, DM-CKD and healthy control groups. Plasma TNF-α, hsCRP and uMCP-1 levels as inflammatory mediators were measured by ELISA, reduced glutathione (GSH), ferric reducing ability of plasma (FRAP) as parameters of antioxidant activity and malondialdehyde (MDA) as marker of oxidative stress, were measured spectrophotometrically. Plasma TNF-α, hsCRP and uMCP-1 were significantly higher in DM-CKD compared to DM and healthy controls. Lipid peroxidation, measured as MDA was significantly higher in patients with DM-CKD as compared to patients with DM and healthy controls. Further, antioxidant capacity of blood measured as FRAP and GSH was found to be significantly lower in patients with DM and DM-CKD as compared to healthy controls (p<0.001). Plasma TNF-α and uMCP-1 showed a significant positive correlation with HbA1c (r=0.441, 0.643), hsCRP (r=0.400, 0.584) and MDA (r=0.423, 0.759) and significant negative correlation with GSH (R=-0.370, -0.800) and FRAP (r=-0.344, -0.684) Increased inflammatory markers viz. TNF-α, hsCRP and uMCP-1 and markers of oxidative stress i.e. increased MDA and decreased GSH and FRAP in DM-CKD suggest an important role of inflammation and oxidative stress in the pathogenesis of renal damage in diabetic patients.
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Affiliation(s)
- Stuti Gupta
- Departments of Biochemistry and Medicine, University College of Medical Sciences (University of Delhi) & GTB Hospital, Delhi, 110095 India
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Liu Y, Jia Z, Liu S, Downton M, Liu G, Du Y, Yang T. Combined losartan and nitro-oleic acid remarkably improves diabetic nephropathy in mice. Am J Physiol Renal Physiol 2013; 305:F1555-62. [PMID: 23946292 DOI: 10.1152/ajprenal.00157.2013] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). The inhibitors of renin-angiotensin-aldosterone system (RAAS) can alleviate some of the symptoms of DN but fail to stop the progression to ESRD. Our previous studies demonstrate renoprotective action of nitro-oleic acid (OA-NO2) in several rodent models of renal disease. Here we examined the therapeutic potential and the underlying mechanism of combination of losartan and OA-NO2 in db/db mice. OA-NO2 was infused at 5 mg·kg(-1)·day(-1) via osmotic minipump, and losartan was incorporated into diet at 10 mg·kg(-1)·day(-1), each administered alone or in combination for 2 wk. Diabetic db/db mice developed progressive albuminuria and glomerulosclerosis, accompanied by podocytes loss, increased indexes of renal fibrosis, oxidative stress, and inflammation. Treatment of the diabetic mice with OA-NO2 or losartan alone moderately ameliorated kidney injury; however, the combined treatment remarkably reduced albuminuria, restored glomerular filtration barrier structure, and attenuated glomerulosclerosis, accompanied with significant suppression of renal oxidative stress and inflammation. These data demonstrate that combination of losartan and OA-NO2 effectively reverses renal injury in DN.
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Affiliation(s)
- Ying Liu
- Univ. of Utah and Veteran Affairs Medical Center, Division of Nephrology and Hypertension, 30 N 1900 E, Rm. 4R312, Salt Lake City, UT 84132.
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Gui D, Huang J, Guo Y, Chen J, Chen Y, Xiao W, Liu X, Wang N. Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression. Cytokine 2013; 61:970-7. [PMID: 23434274 DOI: 10.1016/j.cyto.2013.01.008] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 12/23/2012] [Accepted: 01/04/2013] [Indexed: 11/15/2022]
Abstract
Accumulating evidence suggests that inflammatory processes are involved in the development of diabetic nephropathy (DN). However, there are no effective interventions for inflammation in the diabetic kidneys. Here, we tested the hypothesis that Astragaloside IV(AS-IV), a novel saponin purified from Astragalus membranaceus (Fisch) Bge, ameliorates DN in streptozotocin (STZ)-induced diabetic rats through anti-inflammatory mechanisms. Diabetes was induced with STZ (65 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats were divided into three groups (n=8/each group), namely, diabetic rats, diabetic rats treated with AS-IV at 5 and 10 mgkg(-1)d(-1), p.o., for 8 weeks. The normal rats were chosen as nondiabetic control group (n=8). The rats were sacrificed 10 weeks after induction of diabetes. AS-IV ameliorated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. Renal NF-κB activity, as wells as protein and mRNA expression were increased in diabetic kidneys, accompanied by an increase in mRNA expression and protein content of TNF-α, MCP-1 and ICAM-1 in kidney tissues. The α1-chain type IV collagen mRNA was elevated in the kidneys of diabetic rats. All of these abnormalities were partially restored by AS-IV. AS-IV also decreased the serum levels of TNF-α, MCP-1 and ICAM-1 in diabetic rats. These findings suggest that AS-IV, a novel anti-inflammatory agent, attenuated DN in rats through inhibiting NF-κB mediated inflammatory genes expression.
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Affiliation(s)
- Dingkun Gui
- Department of Nephrology and Rheumatology, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, PR China
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Abstract
Transforming growth factor-β (TGF-β) is a multifunctional regulatory cytokine that is implicated in a variety of kidney diseases, including diabetic nephropathy and chronic transplant rejection, where it promotes stimulation of the extracellular matrix deposition, cell proliferation, and migration. TGF-β exerts its biological functions largely via its downstream complex signaling molecules, Smad proteins. Paradoxically, TGF-β also is essential for normal homeostasis and suppression of inflammation through mechanisms that are yet to be fully elucidated. One feasible mechanism by which TGF-β may exert its beneficial properties is through induction of heme oxygenase-1 (HO-1). Induction of this redox-sensitive enzyme is known to be cytoprotective through its potent antioxidant, anti-inflammatory, and anti-apoptotic properties in different conditions including several kidney diseases. In this overview, recent advances in our understanding of the role of TGF-β in kidney disease, its molecular regulation of HO-1 expression, and the potential role of HO-1 induction as a therapeutic modality in TGF-β-mediated kidney diseases are highlighted.
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Affiliation(s)
- Abolfazl Zarjou
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Abstract
Diabetic nephropathy is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. This review examines the evidence for inflammation in the development and progression of diabetic nephropathy in both experimental and human diabetes, and provides an update on recent novel experimental approaches targeting inflammation and the lessons we have learned from these approaches. We highlight the important role of inflammatory cells in the kidney, particularly infiltrating macrophages, T-lymphocytes and the subpopulation of regulatory T cells. The possible link between immune deposition and diabetic nephropathy is explored, along with the recently described immune complexes of anti-oxidized low-density lipoproteins. We also briefly discuss some of the major inflammatory cytokines involved in the pathogenesis of diabetic nephropathy, including the role of adipokines. Lastly, we present the latest data on the pathogenic role of the stress-activated protein kinases in diabetic nephropathy, from studies on the p38 mitogen activated protein kinase and the c-Jun amino terminal kinase cell signalling pathways. The genetic and pharmacological approaches which reduce inflammation in diabetic nephropathy have not only enhanced our understanding of the pathophysiology of the disease but shown promise as potential therapeutic strategies.
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Insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: Relationship to microvascular complications and bone mineral density. Cytokine 2012; 59:86-93. [DOI: 10.1016/j.cyto.2012.03.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 03/17/2012] [Accepted: 03/21/2012] [Indexed: 11/18/2022]
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Abstract
Despite advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end-stage renal disease in the United States and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the past decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to decrease uric acid levels and assess the impact of such therapy on diabetic kidney disease.
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Affiliation(s)
- Diana I Jalal
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA.
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Leask A. CCN3: a novel anti-fibrotic treatment in end-stage renal disease? J Cell Commun Signal 2012; 6:115-6. [PMID: 22421928 DOI: 10.1007/s12079-012-0162-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 03/02/2012] [Indexed: 01/31/2023] Open
Abstract
Fibrosis is a major cause of end-stage renal disease (ESRD) a progressive loss in renal function that occurs over a period of months or years, is characterized by a decreased capability of the kidneys to excrete waste products. There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. Plasma levels of CCN2, a fibrogenic agent, is a predictor of ESRD and mortality in patients with type 1 diabetic nephropathy. CCN3 has been hypothesized to have antagonistic effects to CCN2 both in vitro and in vivo, including in cultured mesangial cells. In a recent study, van Roeyen and colleagues (Am J Pathol in press, 2012) showed that in vivo overexpression of CCN3 in a model of anti-Thy1.1-induced experimental glomerulonephritis resulted in decreased albuminuria, glomerulosclerosis and reduced cortical collagen type I accumulation. CCN3 enhanced angiogenesis yes suppressed mesangial cell proliferation. Thus CCN3 protein may represent a novel therapeutic approach to help repair glomerular endothelial damage and mesangioproliferative changes and hence prevent renal failure, glomerulosclerosis and tubulointerstitial fibrosis.
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Affiliation(s)
- Andrew Leask
- Departments of Dentistry and Physiology and Pharmacology, Dental Sciences Building, Western University, London, ON, N6A 5C1, Canada,
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Shi MA, Shi GP. Different roles of mast cells in obesity and diabetes: lessons from experimental animals and humans. Front Immunol 2012; 3:7. [PMID: 22566893 PMCID: PMC3341969 DOI: 10.3389/fimmu.2012.00007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 01/09/2012] [Indexed: 12/18/2022] Open
Abstract
Mast cells (MCs) play an important role in allergic hyperresponsiveness and in defending microorganism infections. Recent studies of experimental animals and humans have suggested that MCs participate in obesity and diabetes. MC distribution and activities in adipose tissues may vary, depending on the locations of different adipose tissues. In addition to releasing inflammatory mediators to affect adipose tissue extracellular matrix remodeling and to promote inflammatory cell recruitment and proliferation, MCs directly and indirectly interact and activate adipose tissue cells, including adipocytes and recruited inflammatory cells. Plasma MC protease levels are significantly higher in obese patients than in lean subjects. Experimental obese animals lose body weight after MC inactivation. MC functions in diabetes are even more complicated, and depend on the type of diabetes and on different diabetic complications. Both plasma MC proteases and MC activation essential immunoglobulin E levels are significant risk factors for human pre-diabetes and diabetes mellitus. MC stabilization prevents diet-induced diabetes and improves pre-established diabetes in experimental animals. MC depletion or inactivation can improve diet-induced type 2 diabetes and some forms of type 1 diabetes, but also can worsen other forms of type 1 diabetes, at least in experimental animals. Observations from animal and human studies have suggested beneficial effects of treating diabetic patients with MC stabilizers. Some diabetic patients may benefit from enhancing MC survival and proliferation – hypotheses that merit detailed basic researches and clinical studies.
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Affiliation(s)
- Michael A Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, MA, USA
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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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Yamashita T, Fujimiya M, Nagaishi K, Ataka K, Tanaka M, Yoshida H, Tsuchihashi K, Shimamoto K, Miura T. Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy. FASEB J 2011; 26:1559-68. [PMID: 22198389 DOI: 10.1096/fj.11-183194] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF-α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ-diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-α and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.
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Affiliation(s)
- Tomohisa Yamashita
- Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
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van Roeyen CRC, Ostendorf T, Floege J. The platelet-derived growth factor system in renal disease: an emerging role of endogenous inhibitors. Eur J Cell Biol 2011; 91:542-51. [PMID: 21872965 DOI: 10.1016/j.ejcb.2011.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Revised: 07/05/2011] [Accepted: 07/05/2011] [Indexed: 01/28/2023] Open
Abstract
The platelet-derived growth factor (PDGF) family consists of four isoforms which are secreted as homodimers (PDGF-AA, PDGF-BB, PDGF-CC and PDGF-DD) or heterodimers (PDGF-AB), and two receptor chains (PDGFR-α and -β). All members of the PDGF system are constitutively or inducibly expressed in renal cells and are involved in the regulation of cell proliferation and migration, the accumulation of extracellular matrix proteins and the secretion of pro- and anti-inflammatory mediators. Particular roles have been identified in mediating mesangioproliferative changes, renal interstitial fibrosis and glomerular angiogenesis. Different endogenous inhibitors of PDGF-induced biological responses exist which affect the activation/deactivation of PDGF isoforms, the activity of the PDGFRs, or which block downstream signaling pathways of the autophosphorylated PDGFRs. The novel endogenous inhibitor nephroblastoma overexpressed gene (NOV, CCN3) reduces PDGF-induced cell proliferation and is downregulated by PDGF isoforms itself. Among all identified inhibitors only few "true" PDGF antagonists have been identified. A better understanding of these inhibitors may aid in the design of novel therapeutic approaches to PDGF-mediated diseases.
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Affiliation(s)
- Claudia R C van Roeyen
- Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Pauwelsstr. 30, D-52057 Aachen, Germany.
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Herman-Edelstein M, Thomas MC, Thallas-Bonke V, Saleem M, Cooper ME, Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy. Diabetes 2011; 60:1779-88. [PMID: 21521871 PMCID: PMC3114395 DOI: 10.2337/db10-1110] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis. RESEARCH DESIGN AND METHODS Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-β1 or angiotensin II in the presence or absence of a selective inhibitor of the TGF-β type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes. RESULTS Treatment of cells with TGF-β1 resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (α-smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV α3), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes. CONCLUSIONS In response to TGF-β and other TGF-dependent stimuli, mature podocytes undergo dedifferentiation that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These "pathoadaptive" changes are seen early in the diabetic glomerulus and ultimately contribute to albuminuria, glomerulosclerosis, and podocytopenia.
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Affiliation(s)
- Michal Herman-Edelstein
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Nephrology and Hypertension, Rabin Medical Center-Hasharon Hospital, Ackler School of Medicine Tel-Aviv University, Petach-Tikva, Israel
| | - Merlin C. Thomas
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Vicki Thallas-Bonke
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Moin Saleem
- Academic and Children’s Renal Unit, University of Bristol, Bristol, U.K
| | - Mark E. Cooper
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Phillip Kantharidis
- JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Corresponding author: Phillip Kantharidis,
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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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Awad AS, Rouse MD, Khutsishvili K, Huang L, Bolton WK, Lynch KR, Okusa MD. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int 2011; 79:1090-8. [PMID: 21289599 PMCID: PMC3155206 DOI: 10.1038/ki.2010.544] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.
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Affiliation(s)
- Alaa S. Awad
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
- The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
- Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA
| | - Michael D. Rouse
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Konstantine Khutsishvili
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
- The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Liping Huang
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
- The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - W. Kline Bolton
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
- The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Kevin R. Lynch
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA
| | - Mark D. Okusa
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
- The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA
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Chen KH, Hung CC, Hsu HH, Jing YH, Yang CW, Chen JK. Resveratrol ameliorates early diabetic nephropathy associated with suppression of augmented TGF-β/smad and ERK1/2 signaling in streptozotocin-induced diabetic rats. Chem Biol Interact 2011; 190:45-53. [PMID: 21300041 DOI: 10.1016/j.cbi.2011.01.033] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 01/26/2011] [Accepted: 01/31/2011] [Indexed: 11/30/2022]
Abstract
Diabetic nephropathy (DN) is the major cause of end-stage renal disease. The early changes in DN are characterized by an increased in kidney size, glomerular volume, and kidney function, followed by the accumulation of glomerular extracellular matrix, increased urinary albumin excretion (UAE), glomerular sclerosis, and tubular fibrosis. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats. In the present study, we examined the beneficial effects of RSV on DN and explored the possible mechanism of RSV action. Male Sprague-Dawley rats were injected with streptozotocin at 65mg/kg body weight. The induction of diabetes mellitus (DM) was confirmed by a fasting plasma glucose level ≥300mg/dL and symptoms of polyphagia and polydipsia. The DM rats were treated with or without RSV at 0.75mg/kg body weight 3 times a day for 8 weeks. Animals were sacrificed and kidney histology was examined by microscopy. Urinary albumin excretion, glomerular hypertrophy and expressions of fibronectin, collagen IV, and TGF-β in the glomeruli were alleviated in RSV-treated DM rats, but not in untreated DM rats. In addition, RSV treatment reduced the thickness of the glomerular basement membrane (GBM) to the original thickness and increased nephrin expressions to normal levels in DM rats. Moreover, RSV inhibited phosphorylation of smad2, smad3 and ERK1/2 in diabetic rat kidneys. This is the first report showing that RSV alleviates early glomerulosclerosis in DN through TGF-β/smad and ERK1/2 inhibition. In addition, podocyte injuries of diabetic kidneys are lessened by RSV.
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Affiliation(s)
- Kuan-Hsing Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
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Araoka T, Abe H, Tominaga T, Mima A, Matsubara T, Murakami T, Kishi S, Nagai K, Doi T. Transcription factor 7-like 2 (TCF7L2) regulates activin receptor-like kinase 1 (ALK1)/Smad1 pathway for development of diabetic nephropathy. Mol Cells 2010; 30:209-18. [PMID: 20803090 DOI: 10.1007/s10059-010-0109-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Revised: 05/17/2010] [Accepted: 05/28/2010] [Indexed: 11/29/2022] Open
Abstract
Smad1 has previously been shown to play a key role in the development of diabetic nephropathy (DN), by increasing synthesis of extracellular matrix. However, the regulatory mechanism of Smad1 in DN is still unclear. This study aims to elucidate molecular interactions between activin receptor-like kinase 1 (ALK1)/Smad1 signaling pathway and transcription factor 7-like 2 (TCF7L2) in the progression of DN in vitro and in vivo. The expressions of TCF7L2 and ALK1 were induced by advanced glycation end products (AGEs) in parallel with Smad1, phosphorylated Smad1 (pSmad1), and alpha-smooth muscle actin (α-SMA) through TGF-β1 in cultured mesangial cells. Constitutively active ALK1 increased pSmad1 and α-SMA expressions. The binding of TCF7L2 to ALK1 promoter was confirmed by chromatin immunoprecipitation assay. Furthermore, TCF7L2 induced promoter activity of ALK1. AGEs and TGF-β1 induced a marked increase in TCF7L2 expression in parallel with ALK1. Overexpression of TCF7L2 increased the expressions of ALK1 and Smad1. Inversely, TCF7L2 knockdown by siRNA suppressed α-SMA expression as well as ALK1 and Smad1. The iNOS transgenic mice (iNOS-Tgm), which developed diabetic glomerulosclerosis resembling human diabetic nephropathy, exhibited markedly increased expressions of ALK1, TCF7L2, Smad1, pSmad1, and α-SMA in glomeruli in association with mesangial matrix expansion. These results provide a new evidence that the TCF7L2/ALK1/Smad1 pathway plays a key role in the development of DN.
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Affiliation(s)
- Toshikazu Araoka
- Deapartment of Nephrology, Graduate School of Medicine, Institute of Health-Bio-Science, University of Tokushima, Tokushima, 770-8503, Japan
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