exenatide and Diabetic-Nephropathies

To explore the improvement and mechanism of combination therapy with Exendin-4 (Ex4) and islet transplantation (IT) on the rat model with diabetic nephropathy (DN).. The DN rat model was established by injecting streptozotocin (STZ), supplemented by high-fat and high-glucose feeding. Forty DN rats were assigned to four groups treated with saline, Ex4, IT, and Ex4 combined with IT, respectively, using the healthy rat as normal control. The glomerular filtration barrier (GFB) and renal functions were assessed via the histopathological examination and urinalysis, respectively. Then general indexes, renal fibrosis-related factors, CTGF, TGF-β1, and the anti-renal fibrosis factor, HGF, PI3K/Akt/MTOR signaling pathway-related factors were investigated via immunohistochemical staining and western blotting method.. Body weight, blood glucose level, %HbAlc and other diabetes-related factors were all significantly decreased in combination therapy group compare to all other three DN rat groups. After combination or mono treatment of Ex4 and IT, the GFB structure of DN model rats were all obviously improved compared with saline-treated ones. The 24 h-urine proteins and thickness glomerular basilemma in combination group were obviously down-regulated. The pathological change of podocytes, oxidative stress-related factors, the expression levels of HGF, CTGF and TGF-β1 were all obviously improved in combination group. Furthermore, combined treatment also effectively improved the oxidative stress related indicators, and down-regulated PI3K/Akt/MTOR signaling pathway compare to saline or any mono treatment group.. Combined Ex4 with IT exhibited promising improvement on DN via inhibiting oxidative stress, fibrosis and down-regulating the PI3K/Akt/MTOR signaling pathway in DN rats.

Topics: Animals; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Exenatide; Hypoglycemic Agents; Islets of Langerhans Transplantation; Male; Rats; Rats, Sprague-Dawley; Treatment Outcome

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN.

Topics: Animals; Anthocyanins; Antibodies, Monoclonal; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Exenatide; Guanidines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Failure, Chronic; Mice; Mycophenolic Acid; Oligonucleotides, Antisense; ortho-Aminobenzoates; Peptides; Renin-Angiotensin System; rho-Associated Kinases; Spironolactone; Venoms

Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD).. We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes.. Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m2. After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group.. Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Topics: Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Treatment Outcome

To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).. Exenatide (5 or 10 microg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft-Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min(-1), n = 8), mild RI (51-80 ml min(-1), n = 8), moderate RI (31-50 ml min(-1), n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL.. Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h(-1), respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 microg q.d.).. Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 microg) unsuitable in severe RI or ESRD.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Exenatide; Female; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Peptides; Single-Blind Method; Venoms

Diabetic nephropathy (DN) is one of the devastating complications in diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is one of the incretins secreted from L cells in the intestine. Crocin (a carotenoid component of saffron) has antioxidants properties. We investigated the renal effects of Exendin-4 as a GLP-1 agonist and Crocin in DN.Thirty male rats were divided into five groups: control, type II DM, type II DM + Exendin-4, type II DM + Crocin ‏ and type II DM + Exendine-4 + Crocin. At the end of the experimental period, systolic and diastolic blood pressures were measured, and GFR was calculated. Blood and urine samples were collected for biochemical analysis. Tissue samples were collected from the kidney for histological examination and biochemical measurements of protein expression.Treatment with GLP-1 agonist or Crocin caused a significant improvement in renal function. Better results were achieved with simultaneous administration of both drugs with inhibition of notch signalling pathway and the related proteins.

Topics: Animals; Carotenoids; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Exenatide; Glucagon-Like Peptide 1; Male; Models, Animal; Rats

Diabetic nephropathy is the principal cause of end-stage renal failure and current interventions for its recession remains unsatisfactory. Mesenchymal stem cells (MSCs) hold an attractive source for renovating injured tissues. Unfortunately, limited self-renewal and migration capacity of MSCs after transplantation hinder their clinical applicability which demands a new policy for enhancing their biological functions. This study aimed to investigate whether the renoprotective potential of adipose-derived MSCs (ADMSCs) in diabetic rats could be promoted by exenatide, a glucagon-like peptide-1 (GLP-1) analogue. These effects were studied in type 2 diabetes mellitus rats which were administrated ADMSCs, exenatide or their combination four weeks post-induction. Four weeks later, renal function parameters were evaluated. To address the possible underlying mechanisms, parameters indicating glycolipid metabolism tolerance and oxidative stress biomarkers were assessed in renal tissues alongside evaluation of protein expression of tumor necrosis factor-alpha, transforming growth factor-beta1 and cleaved caspase-3. The results showed that the combined therapy had superior renoprotective effect as evident by significant improvement in kidney function and renal architecture changes through rebalancing of inflammatory, fibrotic and apoptotic markers. Based on these outcomes, ADMSCs with exenatide were supposed to effectively ameliorate diabetic renal dysfunction compared to ADMSCs solely, presenting a promise therapy for diabetic nephropathy with further clinical studies warranted to validate this effect.

Topics: Animals; Blood Glucose; Caspase 3; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Exenatide; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Oxidative Stress; Rats, Wistar; Streptozocin; Subcutaneous Fat; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM).. In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate.. The expressions of UCP-1, PGC-1. Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Topics: 3T3-L1 Cells; 8-Hydroxy-2'-Deoxyguanosine; Adenylate Kinase; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Albuminuria; Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Fibrosis; Gene Expression; Incretins; Kidney; Lipase; Mesangial Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Rats; Real-Time Polymerase Chain Reaction; Triglycerides; Uncoupling Protein 1

Glucagon-like peptide-1 (GLP-1) is a novel antidiabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the human kidney-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analog, liraglutide, in the presence of high glucose. However, most of the previous findings mainly focused on its indirect effect in inhibiting the advanced glycation end products. Here, besides glycemic control, we also demonstrated a stimulatory role of liraglutide in promoting autophagy and relieving oxidative stress in Zucker diabetic fatty rats. The renoprotective effect of liraglutide has been demonstrated by significantly decreasing urinary albumin (

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; HEK293 Cells; Humans; Rats; Rats, Zucker; Signal Transduction; TOR Serine-Threonine Kinases

To investigate the effects of exenatide on renal injury in streptozotocin-induced diabetic rats.. Fifty SD rats were randomly divided into normal control, model, exenatide-1, exenatide-2 and exenatide-3 groups, 10 rats in each group. The diabetic nephropathy model was constructed in later 4 groups. Then, the later 3 groups were treated with 2, 4 and 8 μg/kg exenatide for 8 weeks, respectively. The serum and urine biochemical indexes and oxidative stress and inflammatory indexes in renal tissue were determined.. Compared to the model group, in exenatide-3 group the serum fasting plasma glucose and hemoglobin A1c levels were significantly decreased, the fasting insulin level was significantly increased, the renal index and blood urea nitrogen, serum creatinine and 24 h urine protein levels were significantly decreased, the renal tissue superoxide dismutase and glutathione peroxidase levels were significantly increased, the malondialdehyde level was significantly decreased, and the renal tissue tumor necrosis factor alpha, interleukin 6, hypersensitive C-reactive protein and chemokine (C-C motif) ligand 5 levels were significantly decreased P<0.05).. Exenatide can mitigate the renal injury in diabetic rats. The mechanisms may be related to its resistance of oxidative stress and inflammatory response in renal tissue.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Exenatide; Kidney; Male; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley

Hyperglycemia impairs glucagon-like peptide-1 receptor (GLP-1R) signaling in multiple cell types and thereby potentially attenuates the therapeutic effects of GLP-1R agonists. We hypothesized that the downregulation of GLP-1R by hyperglycemia might reduce the renal-protective effects of GLP-1R agonists in diabetic nephropathy (DN). In this study, we examined the effects of high glucose on the expression of GLP-1R and its signaling pathways in the HBZY-1 rat mesangial cell line. We found that high glucose reduced GLP-1R messenger RNA (mRNA) levels in HBZY-1 cells and in the renal cortex in db/db mice comparing with control groups. In consistence, GLP-1R agonist exendin-4 induced CREB phosphorylation was attenuated by high glucose but not low glucose treatment, which is paralleled with abrogated anti-inflammatory functions in HBZY-1 cells linked with nuclear factor-κB (NF-κB) activation. In consistence, GLP-1R inhibition aggravated the high glucose-induced activation of NF-κB and MCP-1 protein levels in cultured HBZY-1 cells while overexpression of GLP-1R opposite effects. We further proved that metformin restored high glucose-inhibited GLP-1R mRNA expression and decreased high glucose evoked inflammation in HBZY-1 cells. On the basis of these findings, we conclude that high glucose lowers GLP-1R expression and leads to inflammatory responses in mesangial cells, which can be reversed by metformin. These data support the rationale of combinative therapy of metformin with GLP-1R agonists in DN.

Topics: Animals; Cell Line; Chemokine CCL2; Diabetic Nephropathies; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose; Hyperglycemia; Mesangial Cells; Metformin; Mice; NF-kappa B

To evaluate the effectiveness and tolerability of exenatide once weekly (EQW) compared with basal insulin (BI) among injectable-drug-naïve patients with type 2 diabetes mellitus (T2DM) who are elderly or have renal impairment (RI).. Initiators of EQW and BI with T2DM were identified for the period 2012 to 2015 within a US electronic health record database and matched by propensity score. Matched EQW and BI initiators aged ≥65 years or who had RI were compared. Data on weight, glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), blood pressure and lipids were obtained at baseline and quarterly (Q1-Q4) or semi-annually for 1 year after drug initiation. Hypoglycaemia and gastrointestinal symptoms were identified using diagnosis codes and data abstracted from clinical notes.. Among patients aged ≥65 years, HbA1c changed by -0.50 and -0.31 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.6 kg among EQW initiators compared with 0.2 kg among BI initiators. Compared with BI initiators, EQW initiators had a 1.45-fold increased risk of nausea and vomiting. Among patients with RI, HbA1c changed by -0.58 and -0.33 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.9 kg for EQW initiators while BI initiators had no change in weight. EQW initiators had a 1.28-fold increased risk of constipation and diarrhoea compared with BI initiators.. Regardless of age or renal function, the benefits of EQW relative to BI treatment are improved glycaemic control and increased weight loss, which should be weighed against the increased risk of gastrointestinal symptoms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Humans; Injections, Subcutaneous; Insulin; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Treatment Outcome; United States; Young Adult

To investigate the protective effect of exenatide (Ex) on the renal injury in streptozotocin-induced diabetic rats.. Sprague-Dawley rats were randomly divided into 2 groups:normal control group (NC group,. Compared to the DM group,glycolipid metabolic abnormalities in the exenatide-treated groups were significantly ameliorated with lower levels of blood glucose,HbAlc, cholesterol and triglyceride (. Exe-natide has the renal protective effect probably by the mechanisms of inhibition of AGEs production and reduction of oxidative stress in the renal tissues of diabetic rats.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Exenatide; Kidney; Oxidative Stress; Peptides; Protective Agents; Rats; Rats, Sprague-Dawley; Streptozocin; Venoms

To explore effects of exendin-4 on the metabolism of extracellular matrix (ECM) in human mesangial cells (HMC) cultured in the presence of high glucose and explore the possible mechanism.. Human mesangial cells (HMC) were treated with exendin-4 under high glucose conditions. The cell proliferation was observed using CCK8 assay, and the expressions of collagen type I, fibronectin, transforming growth factor-β1 (TGFβ1) expression and extracellular signal- regulated kinase (ERK) signaling pathway activity were assessed using Western blotting.. Exendin-4 inhibited cell proliferation and the expressions of collagen type I, fibronectin and TGFβ1 and reversed ERK phosphorylation in high glucose-induced HMC.. Exendin-4 can regulate ECM metabolism in HMC cultured in high glucose by inhibiting TGFβ1/ERK pathway, suggesting the beneficial effects of exendin-4 in preventing and treating diabetic nephropathy.

Topics: Cell Proliferation; Cells, Cultured; Collagen Type I; Culture Media; Diabetic Nephropathies; Exenatide; Extracellular Matrix; Fibronectins; Glucose; Humans; MAP Kinase Signaling System; Mesangial Cells; Peptides; Phosphorylation; Signal Transduction; Transforming Growth Factor beta1; Venoms

Topics: Animals; Apolipoproteins E; ATP Binding Cassette Transporter 1; Cholesterol; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelial Cells; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Kidney Glomerulus; Male; MAP Kinase Signaling System; Mice; Mice, Knockout; Middle Aged; Mitogen-Activated Protein Kinase 3; Peptides; Phosphatidylinositol 3-Kinases; Proteinuria; Proto-Oncogene Proteins c-akt; Venoms

In this study, we aimed to research the restorative effects of exendin-4, a GLP-1 analog, on renal tubular injury in streptozotocin-induced diabetes model. BALB/c male mice were divided into four groups: non-diabetic, non-diabetic + exendin-4 (3 μg/kg), diabetic and diabetic + exendin-4. In our diabetic model, we observed renal injury mainly in tubular area rather than glomeruli and exendin-4 decreased tubular injury with its glucose lowering effect. Besides, PCNA positive tubular cells, activities of LDH and Na(+)-K(+)-ATPase were also significantly declined by the administration of exendin-4. Furthermore, exendin-4 attenuated the levels of ROS, MDA, 8-OHdG, proinflammatory cytokines (TNF-α, IL-1β), chemokine MCP-1, ICAM-1, and fibrosis-related molecules (transforming growth factor β1 and fibronectin). In consistent with reducing tubular injury, macrophage infiltration and both MCP-1 and ICAM-1 production in tubular cells were decreased. These results indicate that exendin-4 may decrease renal tubular injury seen in the beginning of diabetic nephropathy by decreasing ROS production and inflammation.

Topics: Animals; Chemokine CCL2; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Exenatide; Inflammation; Intercellular Adhesion Molecule-1; Kidney Tubules; L-Lactate Dehydrogenase; Macrophages; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Peptides; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Streptozocin; Tumor Necrosis Factor-alpha; Venoms

Glucagon-like peptide-1 (GLP-1), which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate diabetic nephropathy in experimental models. However, the mechanisms through which GLP-1 modulates renal function remained illdefined. The present study investigated the putative mechanisms underlying effects of exendin-4, a GLP-1 analog, on mesangial cell proliferation and fibronectin.. Rat mesangial cells (MCs) were treated with exendin-4 under high glucose conditions. AMP-activated protein kinase (AMPK) inhibitors (compound C) and agonists (AICAR) were used to analyze the role of this kinase. Cell proliferation was measured using a MTT assay. Fibronectin expression and AMPK-signaling pathway activity were assessed using ELISA and Western blotting, respectively. The production of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinases (TIMP)-2 was evaluated using quantitative real-time RT-PCR.. Exendin-4 inhibited cell proliferation and fibronectin secretion in high glucose-induced MCs. It also caused phosphorylation of AMPK and subsequently increased the ratio of MMP-2 to TIMP-2, which resulted in the degradation of fibronectin. Exendin-4 reversed extracellular signal-regulated kinase (ERK) phosphorylation and enhanced expression of mammalian target of rapamycin (mTOR) in MCs. Moreover, the activation of the AMPK pathway by exendin-4 was induced by AICAR, which was inhibited by compound C.. Exendin-4 exerts an inhibitory effect on cell proliferation and fibronectin secretion in rat MCs, partly through AMPK activation. These results may explain some of the beneficial effects of exendin-4 on the kidney.

Topics: AMP-Activated Protein Kinases; Animals; Cell Proliferation; Diabetic Nephropathies; Exenatide; Gene Expression Regulation; Glucose; Hypoglycemic Agents; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Mesangial Cells; Peptides; Rats; Sweetening Agents; TOR Serine-Threonine Kinases; Venoms

One of the major concerns is a nephropathy in diabetes, which applies many different kinds of medicines. However, required level of the treatment of renal disease has not been achieved.. To investigate and compare the effect of the enalapril and the exenatide on diabetic nephropathy in rats developed diabetes by streptozosin.. 32 male Sprague Dawley rats were divided into 4 groups: (1) Control, (2) Diabetic (DM), (3) DM+ Enalapril, and (4) DM+ exenatide groups. Then, the animals were euthanized and their blood samples were collected by cardiac puncture for blood glucose; blood urea nitrogen (BUN), creatinin, and nephrectomy were performed for histopathologic examination, and urine samples were taken on stick for proteinuria.. Administration of the enalapril or the exenatide in diabetic rats resulted in a significant reduction both fibronectin, induced nitric oxide synthase (i-NOS) expression in glomerular area and urine protein levels. It was shown that both of enalapril and exenatide protected the renal glomerulus more than diabetic group in the nephropathy histopathologically.. The beneficial effects of enalapril and exenatide which reduces fibronectin, i-NOS expression and urine protein levels or increases recovery of glomerules, might be used for preventing the harmful effects of diabetic nephropathy.

Topics: Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Exenatide; Gene Expression Regulation, Enzymologic; Hypoglycemic Agents; Male; Nephrons; Nitric Oxide Synthase Type II; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Exenatide; Female; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Venoms

To investigate the effect of exendin-4 on the expression of monocyte chemoattractant protein-1 (MCP-1) and fibronectin (FN) in rat glomerular mesangial cells in vitro.. Rat glomerular mesangial cells were divided into 5 groups, namely control group, tumor necrosis factor-α (TNF-α) group (10 ng/ml), TNF-α (10 ng/ml)+E1 (1 nmol/L exendin-4) group, TNF-α (10 ng/ml)+E5 (5 nmol/L exendin-4) group, and TNF-α (10 ng/ml)+E10 (10 nmol/L exendin-4) group. After cultured 24 h or 48 h, RNA were extracted to determine the expression of MCP-1 with real-time PCR, the supernatant were collected to determine the expression of MCP-1 and FN with ELISA.. Compared with control group, the cells treated with TNF-α for 24 h showed significantly increase the expression of MCP-1 and FN (P<0.01), exendin-4 significantly reduced the expression of MCP-1 and FN in TNF-α+E5 group and TNF-α+E10 group (P<0.05). After 48h incubation, the expression of MCP-1 and FN increased significantly in TNF-α group (P<0.01), which was lowered by exendin-4 in TNF-α+E1,TNF-α+E5 and TNF-α+E10 groups (P<0.05).. Exendin-4 has an intrinsic capability to concentration- and time-dependently inhibit TNF-α-induced expression of MCP-1 and FN in rat mesangial cells, suggesting the beneficial effect of exendin-4 in preventing and treating diabetic nephropathy.

Topics: Animals; Cells, Cultured; Chemokine CCL2; Diabetic Nephropathies; Exenatide; Glomerular Mesangium; Mesangial Cells; Peptides; Rats; Tumor Necrosis Factor-alpha; Venoms

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.

Topics: Animals; Arginine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Exenatide; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycation End Products, Advanced; Humans; Hypertrophy; Hypoglycemic Agents; Kidney; Kidney Glomerulus; Kidney Tubules; Macrophages; Male; Peptides; Protein-Arginine N-Methyltransferases; Rats; Rats, Wistar; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Receptors, Glucagon; Receptors, Immunologic; Repressor Proteins; RNA, Messenger; Venoms

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Drug Therapy, Combination; Evidence-Based Medicine; Exenatide; Female; Humans; Hypertension; Hypoglycemic Agents; Male; Metformin; Peptides; Venoms

To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A-dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho-c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho-c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4-protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.

Topics: Angiotensin II; Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelium; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptides; Protein Kinase C; Protein Kinase C beta; Proto-Oncogene Proteins c-raf; Receptors, Glucagon; RNA Interference; Signal Transduction; Tissue Culture Techniques; Venoms

Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose.. We administered exendin-4 at 10 μg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro.. Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells.. These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Topics: Animals; Blood Glucose; Blotting, Western; Cell Line; Cell Line, Tumor; Collagen Type IV; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Exenatide; Fluorescent Antibody Technique; Glucagon-Like Peptide-1 Receptor; Humans; Intercellular Adhesion Molecule-1; Male; NF-kappa B; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; Venoms

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Exenatide; Female; Humans; Hypoglycemic Agents; Ischemia; Kidney Glomerulus; Male; Middle Aged; Peptides; Renal Insufficiency; Venoms

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Interactions; Exenatide; Humans; Hypoglycemic Agents; Insulin; Peptides; Venoms

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-beta1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator-activated receptor alpha and GLP-1 receptor-positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Caspase 3; Creatinine; Deoxyguanosine; Diabetic Nephropathies; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Kidney; Lipids; Male; Mice; Mice, Inbred C57BL; Peptides; PPAR alpha; Receptors, Glucagon; Systole; Transforming Growth Factor beta1; Venoms