ABSTRACT
INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. MATERIALS AND METHODS: Five-week-old male Sprague-Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. RESULTS: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. CONCLUSIONS: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Kidney Diseases/drug therapy , Adamantane/analogs & derivatives , Adamantane/pharmacology , Adamantane/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Cyclic AMP/urine , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Diabetic Nephropathies/blood , Diabetic Nephropathies/complications , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/pathology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Disease Models, Animal , Glucagon-Like Peptide 1/blood , Kidney Diseases/complications , Kidney Diseases/metabolism , Kidney Diseases/pathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/pathology , Male , Nitriles/pharmacology , Nitriles/therapeutic use , Protective Agents/pharmacology , Protective Agents/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad(-/-)) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad(-/-) mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad(-/-) mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.
Subject(s)
Adiponectin/metabolism , Albuminuria/metabolism , Podocytes/metabolism , AMP-Activated Protein Kinases , Adiponectin/genetics , Adult , Albumins/metabolism , Animals , Cells, Cultured , Female , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Diseases/urine , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Multienzyme Complexes/metabolism , NADPH Oxidase 4 , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , Obesity/complications , Obesity/urine , Oxidative Stress , Phosphoproteins/genetics , Phosphoproteins/metabolism , Podocytes/cytology , Podocytes/pathology , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/physiology , Zonula Occludens-1 ProteinABSTRACT
Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SR-A(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-beta at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.
Subject(s)
Diabetic Nephropathies/metabolism , Inflammation/genetics , Kidney/metabolism , Scavenger Receptors, Class A/metabolism , Albuminuria , Animals , Collagen Type IV/metabolism , Creatinine/urine , Diabetes Mellitus, Experimental , Diabetic Nephropathies/genetics , Gene Expression , Glycation End Products, Advanced/metabolism , Mice , Mice, Knockout , Osteopontin/metabolism , RNA, Messenger/metabolism , Receptor for Advanced Glycation End Products , Receptors, Immunologic/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Scavenger Receptors, Class A/deficiency , Scavenger Receptors, Class A/genetics , Streptozocin , Transforming Growth Factor beta/metabolismABSTRACT
The recognition that the drivers of matrix accumulation is an appropriate therapeutic target for diabetic nephropathy is now accepted by the nephrology and pharmaceutical communities. Interventions focused around transforming growth factor-beta (TGF-beta) likely will be an important area of clinical investigation in the near future. Understanding the various pathways involved in stimulating TGF-beta in the diabetic kidney is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. In this review we highlight the major pathways involved in stimulating TGF-beta production by increased glucose levels and discuss the therapeutic implications thereof.
Subject(s)
Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Extracellular Matrix Proteins/therapeutic use , Proteoglycans/therapeutic use , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism , Animals , Blood Glucose/metabolism , Decorin , Humans , PrognosisABSTRACT
INTRODUCTION: Macrophages play critical roles in the development of atherosclerosis and diabetic nephropathy as well as many inflammatory diseases. Angiotensin II type 1 receptor antagonists (AIIA) are beneficial for the prevention of atherosclerosis and diabetic nephropathy suggesting that angiotensin II (Ang II) promotes the development of these diseases. It has recently been reported that Ang II exerts proinflammatory actions in vivo and in vitro. This study was aimed to clarify the direct effects of Ang II on monocytes/macrophages. MATERIALS AND METHODS: PMA-treated THP-1 cells, a human monocytic leukaemia cell line, were treated with Ang II (10-6 mol/L) for 24 hours with or without AIIA (CV11974). We evaluated gene expression profiles of these cells using DNA microarray system and quantified them by real-time RT-PCR. RESULTS: DNA microarray revealed that in total 19 genes, including monocyte chemoattractant protein (MCP)-2, were up-regulated by Ang II and down-regulated by AIIA. Real-time RT-PCR showed that up-regulation of MCP-2 with Ang II is blocked by the AIIA (CV11974) but not by an AT2-receptor antagonist. CONCLUSIONS: These results suggest that Ang II directly stimulates MCP-2 expression through AT1-receptors in activated macrophages. Ang II may contribute to the persistence or amplification of microinflammation in vessel walls, heart and kidney. Vasculoprotective or renoprotective effects of AIIA might partly depend on direct anti-inflammatory effects on macrophages.