interleukin-8 and Diabetic-Nephropathies

Diabetic nephropathy is a multifactorial disease. Gene susceptibility, as well as environmental exposure, plays an important role in disease progression. Malaysia is reported to be among the world's second-fastest-growing rates of kidney failure. Diabetic nephropathy has become the main cause of end-stage renal disease in Malaysia. This article is aimed at reviewing genetic studies conducted among diabetic nephropathy patients in the Malaysian population. This review was conducted by searching PubMed, MEDLINE, and Google Scholar databases to identify all relevant papers published in English from March 2022 to April 2022, using the following keywords: diabetes, type 2 diabetes, diabetic nephropathy, diabetic kidney disease, and Malaysia. The case-control study among diabetic patients with and without diabetic nephropathy showed a significant association with diabetic nephropathy in CNDP1, NOS3, and MnSOD genes. In the ethnic subgroup analysis, significant differences for diabetic nephropathy in terms of diabetes duration (≥10 years) were observed for CCL2 rs3917887, CCR5 rs1799987, ELMO1 rs74130, and IL8 rs4073. The IL8 rs4073 was associated only with the Indians, while the CCR5 rs1799987 was associated with the Chinese. In Malays, SLC12A3 Arg913Gln polymorphism and ICAM1 K469E (A/G) polymorphism were found to be associated with diabetic nephropathy. Studies on gene-environment interactions have suggested significant genetic and environmental factors such as smoking, waist circumference, and sex for eNOS rs2070744, PPARGC1A rs8192678, KCNQ1 rs2237895, and KCNQ1 rs2283228 with kidney disease. The genetic variants' contributions differed across ethnic groups. Therefore, a study to validate the genetic variants that are found to be associated with different ethnicities in Malaysia may be important in future studies.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epigenesis, Genetic; Genetic Predisposition to Disease; Humans; Interleukin-8; KCNQ1 Potassium Channel; Malaysia; Polymorphism, Single Nucleotide; Solute Carrier Family 12, Member 3

Chronic renal failure is a progressive and irreversible loss of kidney function, and the hemodialysis (HD) is one of the most common modalities in this regard. Oxidative stresses [like interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α)] and inflammation are the main risk factors associated with cardiovascular diseases and other complications in many organs in hemodialysis patients; meanwhile, antioxidants like alpha lipoic acid (ALA) may reduce the oxidative stress markers and the levels of inflammatory cytokines, so can improve of the patient's quality of life.. In this randomized clinical trial study, 60 HD patients were randomly categorized in two case and control groups. Case group received a daily capsule of 600 mg of ALA supplementation for 8 weeks, and the control group received placebo capsules daily. The serum level of IL-8 and TNF-α was measured in both groups before and after the intervention.. There were no significant differences in age, gender, duration of dialysis, and causative factor for dialysis between both groups (P > 0.05). The mean of IL-8 and TNF-α after the intervention in case group was 26.20 ± 15.34 and 21.25 ± 9.61, respectively; the difference between both groups was not statistically significant (P > 0.05).. Based on the better feeling and other beneficial effects of ALA were found in our study; we can conclude that it is a beneficial and recommended supplement, especially, for diabetic and dialysis patients.

Topics: Adult; Aged; Antioxidants; Diabetic Nephropathies; Dietary Supplements; Double-Blind Method; Female; Humans; Interleukin-8; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thioctic Acid; Tumor Necrosis Factor-alpha

End-stage renal disease (ESRD) due to type 2 diabetic nephropathy is a very common condition which is increasing in prevalence, and is associated with high global levels of mortality and morbidity. Both proteinuria and transforming growth factor-β (TGF-β) may contribute to the development of ESRD in patients with diabetic nephropathy. Experimental studies indicate that turmeric improves diabetic nephropathy by suppressing TGF-β. Therefore, this study investigated the effects of turmeric on serum and urinary TGF-β, interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α), as well as proteinuria, in patients with overt type 2 diabetic nephropathy.. A randomized, double-blind and placebo-controlled study was carried out in the Diabetes Clinic of the Outpatient Department of Shiraz University of Medical Sciences on 40 patients with overt type 2 diabetic nephropathy, randomized into a trial group (n = 20) and a control group (n = 20). Each patient in the trial group received one capsule with each meal containing 500 mg turmeric, of which 22.1 mg was the active ingredient curcumin (three capsules daily) for 2 months. The control group received three capsules identical in colour and size containing starch for the same 2 months.. Serum levels of TGF-β and IL-8 and urinary protein excretion and IL-8 decreased significantly comparing the pre- and post-turmeric supplementation values. No adverse effects related to turmeric supplementation were observed during the trial.. Short-term turmeric supplementation can attenuate proteinuria, TGF-β and IL-8 in patients with overt type 2 diabetic nephropathy and can be administered as a safe adjuvant therapy for these patients.

Topics: Administration, Oral; Curcuma; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dietary Supplements; Double-Blind Method; Female; Humans; Interleukin-8; Male; Middle Aged; Phytotherapy; Proteinuria; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in DN pathogenesis.. The purpose of the present study was to explore the role and mechanism of lncRNA tetratricopeptide repeat domain 2B antisense RNA 1 (TTC28-AS1) in DN.. Cell viability and apoptosis were assessed by the Cell Counting-8 Kit (CCK-8) assay and flow cytometry, respectively. The levels of TTC28-AS1, miR-320a and CD2-associated protein (CD2AP) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-8 were gauged by enzyme-linked immunosorbent assay (ELISA). Targeted relationship between miR-320a and TTC28-AS1 or CD2AP was evaluated by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays.. Our data indicated that high glucose (HG) induced HK-2 cell damage by the repression of cell viability and autophagy and the enhancement of cell apoptosis, fibrosis and pro-inflammatory cytokines production. TTC28-AS1 was down-regulated and miR-320a was up-regulated in HG-induced HK-2 cells. TTC28-AS1 overexpression or miR-320a knockdown alleviated HG-induced damage in HK-2 cells. MiR-320 was a molecular mediator of TTC28-AS1 in regulating HG-induced HK-2 cell damage. Moreover, TTC28-AS1 functioned as a post-transcriptional regulator of CD2AP expression by miR-320a. MiR-320a knockdown relieved HG-induced damage in HK-2 cells by up-regulating CD2AP.. Our findings suggest that TTC28-AS1 attenuates HG-induced damage in HK-2 cells at least partially by targeting the miR-320a/CD2AP axis, highlighting its role as a promising therapeutic approach for DN treatment.

Topics: Adaptor Proteins, Signal Transducing; Cell Line; Cytoskeletal Proteins; Diabetic Nephropathies; Glucose; Humans; Interleukin-8; MicroRNAs; RNA, Long Noncoding; Tumor Necrosis Factor-alpha

Inflammation has a major role in diabetic kidney disease. We thus investigated the role of the IL-8-CXCR1/2 axis in favoring kidney damage in diabetes.. Urinary IL-8 levels were measured in 1247 patients of the Joslin Kidney Study in type 2 diabetes (T2D). The expression of IL-8 and of its membrane receptors CXCR1/CXCR2 was quantified in kidney tissues in patients with T2D and in controls. The effect of CXCR1/2 blockade on diabetic kidney disease was evaluated in db/db mice.. IL-8 urinary levels were increased in patients with T2D and diabetic kidney disease, with the highest urinary IL-8 levels found in the patients with the largest decline in glomerular filtration rate, with an increased albumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increased in patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured human immortalized podocytes in vitro. Finally, in diabetic db/db mice and in podocytes in vitro, CXCR1/2 blockade mitigated albuminuria, reduced mesangial expansion, decreased podocyte apoptosis and reduced DNA damage.. The IL-8- CXCR1/2 axis may have a role in diabetic kidney disease by inducing podocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease.

Topics: Adult; Animals; Case-Control Studies; Cells, Cultured; Cohort Studies; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Interleukin-8; Italy; Kidney; Mice; Mice, Inbred C57BL; Mice, Transgenic; Podocytes; Receptors, CXCR; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Signal Transduction

To evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction.. In this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed.. Pro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.

Topics: Aged; Albuminuria; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Inflammation; Interleukin-18; Interleukin-1alpha; Interleukin-8; Kidney Tubules, Proximal; Middle Aged; Podocytes

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Inflammatory mediators have been implicated in the pathogenesis of DN, thus considered an inflammatory disease. However, further studies are required to assess the renal damage caused by the action of these molecules. Therefore, the objective of this study was to analyze the expression of cytokines and chemokines in renal biopsies from patients with DN and to correlate it with interstitial inflammation and decreased renal function.. Forty-four native renal biopsies from patients with DN and 23 control cases were selected. In situ expression of eotaxin, MIP-1α (macrophage inflammatory protein-1α), IL-8 (interleukin-8), IL-4, IL-10, TNF-α (tumor necrosis factor-α), TNFR1 (tumor necrosis factor receptor-1), IL-1β, and IL-6 were evaluated by immunohistochemistry.. The DN group showed a significant increase in IL-6 (p < 0.0001), IL-1β (p < 0.0001), IL-4 (p < 0.0001) and eotaxin (p = 0.0012) expression, and a decrease in TNFR1 (p = 0.0107) and IL-8 (p = 0.0262) expression compared to the control group. However, there were no significant differences in IL-10 (p = 0.4951), TNF-α (p = 0.7534), and MIP-1α (p = 0.3816) expression among groups. Regarding interstitial inflammation, there was a significant increase in IL-6 in scores 0 and 1 compared to score 2 (p = 0.0035), in IL-10 in score 2 compared to score 0 (p = 0.0479), and in eotaxin in score 2 compared to scores 0 and 1 (p < 0.0001), whereas IL-8 (p = 0.0513) and MIP-1α (p = 0.1801) showed no significant differences. There was a tendency for negative correlation between eotaxin and estimated glomerular filtration rate (eGFR) (p = 0.0566).. Our results indicated an increased in situ production of cytokines and chemokines in DN, including IL-6, IL-1β, IL-4, and eotaxin. It was observed that, possibly, eotaxin may have an important role in the progression of interstitial inflammation in DN and in eGFR decrease of these patients.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Chemokine CCL11; Chemokine CCL24; Chemokine CCL26; Chemokine CCL3; Chemokines; Cytokines; Diabetic Nephropathies; Female; Humans; Immunohistochemistry; Interleukin-10; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Kidney; Male; Middle Aged; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Young Adult

The aim of this study was to explore the effect of micro ribonucleic acid (miR)-133 on kidney injury in rats with diabetic nephropathy (DN) through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway.. The model of DN was first established in rats. Blood glucose, renal index, urinary micro-albumin (UMA), and creatinine clearance rate (CCr) were detected. Meanwhile, the protein expression levels of miR-133, kidney injury molecule-1 (KIM-1) and anti-inflammatory cytokine interleukin-8 (IL-8) were measured using Western blotting. Human renal proximal tubular epithelial cell line human kidney-2 (HK-2) was treated with high glucose to simulate DN cells in vivo. Subsequently, Western blotting was performed to detect the protein expression of KIM-1. After HK-2 cells were treated with high glucose and silenced miR-133 for 24 h, the expression changes in KIM-1 was evaluated.. In DN group, blood glucose, renal index, UMA, and CCr were all markedly higher than those of control group. This indicated the successful establishment of DN model in rats. The expression level of miR-133 was significantly up-regulated in DN model rats. Meanwhile, the downstream protein phosphorylated-EPK (p-EPK) showed a significantly increasing trend as well. Additionally, the protein expressions of KIM-1 and IL-8 were notably elevated. High-glucose-treated HK-2 cells showed significantly up-regulated expression levels of miR-133, KIM-1, and IL-8. After 24 h of combined treatment with high glucose and miR-133 silence, the expressions of KIM-1 and IL-8 were markedly down-regulated.. MiR-133 may be related to the occurrence and development of DN. The silence of miR-133 inhibits kidney injury in DN via the MAPK/ERK signaling pathway. Our findings suggest that miR-133 may be an effective target for the treatment of DN.

Topics: Acute Kidney Injury; Animals; Cell Line; Diabetic Nephropathies; Disease Models, Animal; Hepatitis A Virus Cellular Receptor 1; Humans; Interleukin-8; Male; MicroRNAs; Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley

Recent studies suggest that chronic inflammatory responses are important in the development of diabetic nephropathy (DN). Various inflammatory and angiogenesis molecules affect the pathogenesis and progression of DN. Inflammation damages the microcirculation and causes kidney damage. In the present study, we studied changes in interleukin-8 (IL-8) and soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels in patients with DN, and investigated the clinical significance of these two inflammatory factors.. Participants were categorized into healthy controls (n = 30) and patients with type 2 diabetes mellitus (n = 124). The type 2 diabetes mellitus group was further subdivided into the normoalbuminuria (n = 34), microalbuminuria (MAU; n = 46,) and proteinuria (MaAU; n = 44,) groups. Patients with DN were included in the MAU and MaAU groups. Total cholesterol, triglyceride, low-density lipoprotein cholesterol, glycosylated hemoglobin, fasting blood glucose, 2-h postprandial blood glucose, blood urea nitrogen, serum creatinine, 24-h urine microalbumin, IL-8 and sTWEAK levels were measured. Logistic regression was used to analyze the factors associated with proteinuria.. In the healthy controls, normoalbuminuria, MAU and MaAU groups, we found that IL-8 levels increased, whereas sTWEAK levels decreased (P < 0.05). IL-8 might be an independent risk factor and serum sTWEAK a protective factor for MAU and MaAU. Serum levels of sTWEAK, IL-8 and microalbumin were significantly correlated in the MAU and MaAU groups.. Serum IL-8 and sTWEAK levels might be markers that can be used for an early diagnosis of DN.

Topics: Adult; Aged; Apoptosis; Biomarkers; Cross-Sectional Studies; Cytokine TWEAK; Diabetic Nephropathies; Female; Humans; Interleukin-8; Male; Middle Aged

Inflammation is recognized as a crucial contribution to diabetic nephropathy (DN). CXCL8 binds to its CXC chemokine receptors (CXCR1 and CXCR2) for recruiting neutrophil infiltration and initiates tissue inflammation. Therefore, we explored the effect of CXCR1 and CXCR2 inhibition on DN. This was achieved by CXCL8(3-72)K11R/G31P (G31P), an antagonist of CXCL8 that has exhibited therapeutic efficacy in inflammatory diseases and malignancies. In this study, we found that renal leukocyte accumulation and rapid increases of CXCL8 occurred in high-fat diet/streptozocin-induced diabetic mice. G31P effectively reduced urine volume, urine albumin/creatinine ratio, blood urea nitrogen, and creatinine clearance rate in mice with diabetes. In addition, renal histopathologic changes including mesangial expansion, glomerulosclerosis, and extracellular matrix deposition were partially moderated in G31P-treated diabetic mice. Furthermore, G31P attenuated renal inflammation and renal fibrosis of diabetic mice by inhibiting proinflammatory and profibrotic elements. G31P also inhibited high glucose-induced inflammatory and fibrotic factor upregulation in human renal mesangial cells. At the molecular level, G31P inhibited activation of CXCR1/2 downstream signaling JAK2/STAT3 and ERK1/2 pathways in in vitro and in vivo experiments. Our results suggest blockade of CXCR1/2 by G31P could confer renoprotective effects that offer potential therapeutic opportunities in DN.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Glucose; Hypoglycemic Agents; Interleukin-8; Male; Mesangial Cells; Mice; Mice, Inbred C57BL; Peptide Fragments; Streptozocin

Background We evaluated the association of cardiac adipose tissue including epicardial adipose tissue and pericardial adipose tissue with incident cardiovascular disease and mortality, coronary artery calcium, carotid intima media thickness and inflammatory markers. Design A prospective study of 200 patients with type 2 diabetes and elevated urinary albumin excretion rate (UAER). Methods Cardiac adipose tissue was measured from baseline echocardiography. The composite endpoint comprised incident cardiovascular disease and all-cause mortality. Coronary artery calcium, carotid intima media thickness and inflammatory markers were measured at baseline. Cardiac adipose tissue was investigated as continuous and binary variable. Analyses were performed unadjusted (model 1), and adjusted for age, sex (model 2), body mass index, low-density lipoprotein cholesterol, smoking, glycated haemoglobin, and systolic blood pressure (model 3). Results Patients were followed-up after 6.1 years for non-fatal cardiovascular disease ( n = 29) or mortality ( n = 23). Cardiac adipose tissue ( p = 0.049) and epicardial adipose tissue ( p = 0.029) were associated with cardiovascular disease and mortality in model 1. When split by the median, patients with high cardiac adipose tissue had a higher risk of cardiovascular disease and mortality than patients with low cardiac adipose tissue in unadjusted (hazard ratio 1.9, confidence interval: 1.1; 3.4, p = 0.027) and adjusted (hazard ratio 2.0, confidence interval: 1.1; 3.7, p = 0.017) models. Cardiac adipose tissue ( p =  0.033) was associated with baseline coronary artery calcium (model 1) and interleukin-8 (models 1-3, all p < 0.039). Conclusions In type 2 diabetes patients without coronary artery disease, high cardiac adipose tissue levels were associated with increased risk of incident cardiovascular disease or all-cause mortality even after accounting for traditional cardiovascular disease risk factors. High cardiac adipose tissue amounts were associated with subclinical atherosclerosis (coronary artery calcium) and with the pro-atherogenic inflammatory marker interleukin-8.

Topics: Adipose Tissue; Adiposity; Aged; Albuminuria; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Coronary Angiography; Denmark; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Echocardiography; Female; Humans; Incidence; Inflammation Mediators; Interleukin-8; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Nonlinear Dynamics; Pericardium; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors

The aim of this conventional case-control study was to investigate the prevalence and relationship between Helicobacter pylori infection in type 2 diabetes mellitus (DM) and diabetic nephropathy (DN).. A total of 241 type 2 DM patients and 69 non-diabetic subjects with dyspeptic symptoms were enrolled in the study. Gastroduodenal lesions were observed by gastrointestinal endoscopy and the presence of H. pylori was identified by rapid urease test and serum IgG antibodies to H. pylori. According to the urinary albumin excretion rate (UAE), patients were classified into diabetes mellitus group (DM group, with UAE <30 mg/24h); diabetic nephropathy group 1 (DN group 1, with UAE 30 mg/24 h to <300 mg/24 h); and diabetic nephropathy group 2 (DN group 2 ≥ 300 mg/24 h). The 69 non-diabetic subjects were used as control group. The serum levels of inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-8 were determined using ELISA.. The prevalence of H. pylori infection in DN group 1 and DN group 2 was 45/72 (62.5%) and 34/53 (64.15%), respectively, which was significantly higher than in control [28/65 (43.1%)] and DM groups [42.9% (27/63)]. No significant differences of H. pylori prevalence were detected between DN groups as well as DM and control groups. Interestingly, in both DN groups, higher levels of IL-8, TNF-α and urinary albumin excretion rate were found in H. pylori positive subjects.. Diabetic nephropathy patients are more susceptible to H. pylori infection. Our data support an association between H. pylori infection and diabetic nephropathy.

Topics: Adult; Albuminuria; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-8; Male; Middle Aged; Prevalence; Tumor Necrosis Factor-alpha

The evolution of diabetic nephropathy is incompletely accounted by current clinical tools. New biomarkers may refine patient assessment and help monitor therapy. We compared the added predictive value of 7 candidate inflammatory urinary biomarkers to known risk factors of progression.. We prospectively followed 83 patients with overt diabetic nephropathy for a median 2.1 years and obtained repeated measurements of proteinuria, IL-1β, IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and PAI-1.. Patients had an initial estimated glomerular filtration rate of 25 ± 9 mL/min/1.73 m(2), blood pressure of 142/69 mmHg and used a median of 4 anti-hypertensive medications over the course of the study. The observed rate of renal function decline was 2.9 ± 3.0 mL/min/1.73 m(2)/year. All urinary biomarkers levels were collinear and for each one except IL-1β, elevated levels predicted a more rapid progression. MCP-1 was the only biomarker increasing during follow-up, which also correlated with a worst outcome. Using multivariate linear regression adjusting for clinical risk factors of progression, urinary MCP-1 and TGF-β1 predicted progression independently and additively to the degree of proteinuria. We dichotomized these 3 biomarkers and observed a renal function decline with 0, 1, 2 or 3 elevated biomarkers of -0.8 ± 1.4, -2.1 ± 2.1, -4.2 ± 2.8 and -6.0 ± 2.8 mL/min/1.73 m(2)/year, respectively (p<0.001).. Multiple urinary biomarkers predict outcome in overt diabetic nephropathy. However, urinary MCP-1 and TGF-β1 are also independent and additive to proteinuria in predicting the rate of renal function decline and could serve as useful clinical tools in patient risk stratification.

Topics: Biomarkers; Chemokine CCL2; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Inflammation; Interleukin-6; Interleukin-8; Plasminogen Activator Inhibitor 1; Prospective Studies; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Diabetic glomerulosclerosis is the hardening of the renal glomeruli that can lead to kidney failure. In the early stage of glomerulosclerosis occur renal mesangial expansion and renal filtration dysfunction. Purple corn has been classified as a functional food and is rich in anthocyanins exerting potential disease-preventive activities. The in vitro study using human renal mesangial cells examined that anthocyanin-rich purple corn butanol fraction (PCB) can attenuate high glucose (HG)-promoted mesangial cell proliferation and matrix accumulation.. Cells were cultured for 3 days in media containing 33 mM glucose in the presence of 1-20 μg/mL PCB. In the in vivo animal study, db/db mice were treated with 10 mg/kg anthocyanin-rich polyphenolic extracts of purple corn (PCE) for 8 weeks.. HG enhanced mesangial production of the fibrosis biomarkers of collagen IV and connective tissue growth factor (CTGF), which was markedly attenuated by adding PCB. Such mesangial fibrosis entailed interleukin-8 activation via eliciting Tyk2-STAT signaling pathway. PCB dampened HG-promoted mesangial hyperplasia that appeared to be attributed to increased expression of platelet-derived growth factor. The 8-week administration of PCE lowered plasma glucose level of db/db mice and ameliorated severe albuminuria. Moreover, PCE lessened collagen fiber accumulation in kidney glomeruli and CTGF expression via retarding TGF-β signaling. Protein expressions of nephrin and podocin, key proteins for filtration barrier function of the glomerular capillary wall, were repressed by treating mice with PCE.. Purple corn may be a potent therapeutic agent for the treatment for diabetes-associated glomerulosclerosis accompanying proteinuria and kidney filtration dysfunction.

Topics: Albuminuria; Animals; Anthocyanins; Biomarkers; Blood Glucose; Cell Proliferation; Collagen Type IV; Connective Tissue Growth Factor; Diabetic Nephropathies; Fibrosis; Humans; Interleukin-8; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mesangial Cells; Mice; Plant Extracts; Platelet-Derived Growth Factor; Proteinuria; Signal Transduction; STAT Transcription Factors; Transforming Growth Factor beta; TYK2 Kinase; Zea mays

Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. In early DN, renal injury and macrophage accumulation take place in the pathological environment of glomerular vessels adjacent to renal mesangial cells expressing proinflammatory mediators. Purple corn utilized as a daily food is rich in anthocyanins exerting disease-preventive activities as a functional food. This study elucidated whether anthocyanin-rich purple corn extract (PCA) could suppress monocyte activation and macrophage infiltration. In the in vitro study, human endothelial cells and THP-1 monocytes were cultured in conditioned media of human mesangial cells exposed to 33 mM glucose (HG-HRMC). PCA decreased the HG-HRMC-conditioned, media-induced expression of endothelial vascular cell adhesion molecule-1, E-selectin, and monocyte integrins-β1 and -β2 through blocking the mesangial Tyk2 pathway. In the in vivo animal study, db/db mice were treated with 10 mg/kg PCA daily for 8 wk. PCA attenuated CXCR2 induction and the activation of Tyk2 and STAT1/3 in db/db mice. Periodic acid-Schiff staining showed that PCA alleviated mesangial expansion-elicited renal injury in diabetic kidneys. In glomeruli, PCA attenuated the induction of intracellular cell adhesion molecule-1 and CD11b. PCA diminished monocyte chemoattractant protein-1 expression and macrophage inflammatory protein 2 transcription in the diabetic kidney, inhibiting the induction of the macrophage markers CD68 and F4/80. These results demonstrate that PCA antagonized the infiltration and accumulation of macrophages in diabetic kidneys through disturbing the mesangial IL-8-Tyk-STAT signaling pathway. Therefore, PCA may be a potential renoprotective agent treating diabetes-associated glomerulosclerosis.

Topics: Animals; Anthocyanins; Diabetes Mellitus, Type 2; Diabetic Nephropathies; E-Selectin; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Intercellular Adhesion Molecule-1; Interleukin-8; Kidney; Macrophages; Mice; Monocytes; Plant Extracts; Signal Transduction; Vascular Cell Adhesion Molecule-1; Zea mays

Elevated urinary albumin excretion in patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy.

Topics: Acetylglucosaminidase; Adult; Albuminuria; Biomarkers; Case-Control Studies; Chemokine CCL2; Chemokine CXCL10; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Hepatitis A Virus Cellular Receptor 1; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Receptors, Virus; Remission, Spontaneous

The receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling pathway (RANKL/RANK/OPG signaling) is implicated in the osteolysis associated with diabetic Charcot neuroarthropathy (CN); however, the links with medial arterial calcification (MAC) seen in people with CN are unclear. This study aimed to investigate the role of RANKL/OPG in MAC in patients with CN.. Enzyme-linked immunosorbent assay and Bio-plex multiarray technology were used to quantify a range of cytokines, including RANKL and OPG in sera from 10 patients with diabetes, 12 patients with CN, and 5 healthy volunteers. Human tibial artery segments were immunohistochemically stained with Alizarin red and human RANKL antibody. Human vascular smooth muscle cells (VSMCs) were also explanted from arterial segments for in vitro studies.. We demonstrate colocalization and upregulation of RANKL expression in areas displaying MAC. Systemic levels of RANKL, OPG, and inflammatory cytokines (interleukin-8, granulocyte colony-stimulating factor) were elevated in those with CN compared with diabetic patients and healthy control subjects. Human VSMCs cultured in CN serum showed accelerated osteoblastic differentiation (alkaline phosphatase activity) and mineralization (alizarin red staining) compared with cells treated with diabetic or control serum (P < 0.05). Coincubation with OPG, the decoy receptor for RANKL, attenuated osteogenic differentiation of VSMCs and was independent of a high calcium-phosphate milieu. The accelerated mineralization induced by RANKL and CN serum correlated with nuclear translocation of nuclear factor-κB, a process abrogated by OPG.. Our data provide direct evidence that RANKL/RANK/OPG signaling is modulated in patients with CN and plays a role in vascular calcification. This study highlights this pathway as a potential target for intervention.

Topics: Aged; Calcinosis; Cell Differentiation; Cells, Cultured; Charcot-Marie-Tooth Disease; Diabetic Nephropathies; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-8; Male; Middle Aged; Muscle, Smooth, Vascular; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

The aim of our study was to examine serum markers of the TNF and Fas pathways for association with cystatin-C based estimated glomerular filtration rate (cC-GFR) in subjects with type 1 diabetes (T1DM) and no proteinuria.. The study group (the 2nd Joslin Kidney Study) comprised patients with T1DM and normoalbuminuria (NA) (n = 363) or microalbuminuria (MA) (n = 304). Impaired renal function (cC-GFR <90 ml/min) was present in only 10% of patients with NA and 36% of those with MA. We measured markers of the tumor necrosis factor alpha (TNFalpha) pathway [TNFalpha, soluble TNF receptor 1 (sTNFR1), and 2 (sTNFR2)], its downstream effectors [soluble intercellular and soluble vascular adhesion molecules (sICAM-1 and sVCAM-1), interleukin 8 (IL8/CXCL8), monocytes chemoattractant protein-1 (MCP1), and IFNgamma inducible protein-10 (IP10/CXCL10)], the Fas pathway [soluble Fas (sFas) and Fas ligand (sFasL)], CRP, and IL6.. Of these, TNFalpha, sTNFRs, sFas, sICAM-1, and sIP10 were associated with cC-GFR. However, only the TNF receptors and sFas were associated with cC-GFR in multivariate analysis. Variation in the concentration of the TNF receptors had a much stronger impact on GFR than clinical covariates such as age and albumin excretion.. Elevated concentrations of serum markers of the TNFalpha and Fas-pathways are strongly associated with decreased renal function in nonproteinuric type 1 diabetic patients. These effects are independent of those of urinary albumin excretion. Follow-up studies are needed to characterize the role of these markers in early progressive renal function decline.

Topics: Adult; Albuminuria; Apoptosis; Biomarkers; C-Reactive Protein; Chemokine CCL2; Chemokine CXCL10; Cross-Sectional Studies; Cystatin C; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fas Ligand Protein; fas Receptor; Female; Glomerular Filtration Rate; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Kidney; Male; Middle Aged; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients.. Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002).. The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

Topics: Adult; Aged; C-Reactive Protein; Chemokine CCL2; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; India; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, CCR5; Regression Analysis; Risk Factors; Transforming Growth Factor beta1

We aimed to evaluate the relationship between interleukin-8 and the oxidant-antioxidant system in end-stage renal failure patients with and without diabetes mellitus undergoing regular hemodialysis treatment.. Plasma levels of malondialdehyde and whole blood reduced glutathione were measured as markers of the oxidant and antioxidant systems, respectively. Plasma interleukin-8 levels were measured by enzyme-linked immunosorbent assay.. When compared with controls, plasma interleukin-8 levels were elevated in both diabetic and nondiabetic end-stage renal disease patients. Plasma malondialdehyde levels were statistically significantly higher in end-stage renal disease patients with and without diabetes mellitus than they were in controls; however, reduced glutathione levels were statistically significantly lower in diabetic and nondiabetic end-stage renal disease patients than they were controls.. In end-stage renal disease patients with and without diabetes mellitus, elevated interleukin- 8 levels and decreased reduced glutathione levels may be attributed to increased oxidative stress due to inflammation. In other words, increased reactive oxygen species may induce interleukin-8 production and result in diminished reduced glutathione levels. Our data suggest a relationship between interleukin- 8 and the oxidant-antioxidant system in end-stage renal failure patients.

Topics: Adult; Antioxidants; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Female; Glutathione; Humans; Interleukin-8; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidants

The effects of advanced glycation end products (AGE) in the form of glycated albumin (GA) on the proinflammatory phenotype of cultured renal proximal tubular epithelial cells (PTEC) and the therapeutic potential of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist were studied. Human PTEC were exposed to medium alone or supplemented with albumin or GA with or without previous addition of rosiglitazone (0.1 to 0.5 microM). Exposure to GA (up to 0.5 mg/ml) but not the equivalent dose of neat albumin significantly upregulated both mRNA and protein expression of IL-8 and soluble intercellular adhesion molecule-1 (sICAM-1) in a dose- and time-dependent manner. Using immunohistochemistry, ICAM-1 signals were detected in the tubular epithelia and peritubular capillaries in association with AGE deposition and leukocyte infiltration, whereas IL-8 staining was localized in the tubular epithelia of human diabetic kidney biopsies. Also in a dose-dependent manner, GA (0.5 mg/ml) but not albumin caused nuclear translocation of NF-kappaB and activation of mitogen-activated protein kinase (MAPK) p44/p42 and signal transducer and activator of transcription (STAT-1). Inhibition of these pathways with pyrrolidine dithiocarbamate, PD 98059, and fludarabine, respectively, attenuated GA-induced IL-8 secretion. Rosiglitazone dose-dependently attenuated GA-induced IL-8 and ICAM-1 signals in PTEC and completely abolished GA-induced STAT-1 signals but had no effect on NF-kappaB and MAPK activation. These findings suggest that AGE stimulate renal tubular expression of adhesion molecule and chemokine that together may account for the transmigration of inflammatory cells into the interstitial space during diabetic tubulopathy. Such proinflammatory phenotype may be partially modified by PPAR-gamma ligation through STAT-1 inhibition independent of NF-kappaB transcriptional activity and MAPK signaling.

Topics: Cell Line; Diabetic Nephropathies; Enzyme Inhibitors; Epithelial Cells; Humans; Immunohistochemistry; Interleukin-8; Kidney; MAP Kinase Signaling System; NF-kappa B; PPAR gamma; RNA, Messenger; Rosiglitazone; Signal Transduction; STAT1 Transcription Factor; Thiazolidinediones

We examined the correlation among the levels of urinary monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), hyperglycemia, and renal injuries in patients with type 2 diabetic nephropathy. The levels of urinary MCP-1, IL-8, protein excretion, blood urea nitrogen (BUN), serum creatinine (s-Cr), glycohemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) were measured in 24 patients with type 2 diabetic nephropathy and 14 healthy adults as controls. Diabetic nephropathy was classified into three stages: stage 1 = normoalbuminuric, stage 2 = microalbuminuric, and stage 3 = macroalbuminuric. All of the patients showed normal ranges in renal function tests. Levels of urinary MCP-1 in all patients with diabetic nephropathy were significantly higher than those in healthy adults (P < 0.05). The levels of urinary MCP-1 in patients with diabetic nephropathy increased gradually according to the clinical stage of this disease. In contrast, the levels of urinary IL-8 in patients with diabetic nephropathy increased in stages 2 and 3. There was a significant correlation between the levels of urinary IL-8 and those of HbA1c. High glucose may stimulate MCP-1 and/or IL-8 production and their excretion into the urine independently of the phases or pathological lesions of this disease. It appears that IL-8 increased in the early stage of diabetic nephropathy, and MCP-1 increased in the advanced stage of this disease. It was concluded that measurement of urinary MCP-1 and IL-8 may be useful for evaluating the degree of renal injuries in patients with type 2 diabetic nephropathy.

Topics: Analysis of Variance; Blood Glucose; Case-Control Studies; Chemokine CCL2; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8