Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation

Abstract

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM+pio). Diabetes was induced by injection with streptozotocin (STZ). The DM+pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-beta, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-kappaB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-gamma was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-kappaB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB. However, pioglitazone did not show the changes in the presence of PPAR-gamma antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-kappaB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

“…25,26,75,76,80,81 At the same time, it has been reported that NF-kB activation induces TGF-b production. [82][83][84] Thus, there is a potential positive feedback mechanism between TGF-b production and NF-kB activation that enhances the fibrotic process. (vi) Furthermore, we used RT-qPCR and protein detection by western blot to demonstrate that H 2 O 2 induces the expression and secretion of TGF-b1 and TGF-b2, and it has been clearly demonstrated that TGF-b1 and TGF-b2 induce the conversion of ECs into myofibroblasts.…”

Change in Albuminuria and eGFR Following Insulin Sensitization Therapy Versus Insulin Provision Therapy in the BARI 2D Study

“…Sobel et al (15) reported that, in BARI 2D subjects, IS as opposed to IP treatment led to changes in biomarker profiles that were indicative of a profibrinolytic, antithrombotic, and antiinflammatory state. Peroxisome proliferator-activated receptors are widely expressed in the kidney, and peroxisome proliferator-activated receptor gamma agonists have renoprotective effects in experimental models of diabetic kidney disease (16,17). Administration of TZDs to insulin-deficient and -resistant diabetic rats ameliorated albuminuria and histologic hallmarks of diabetic nephropathy (18,19).…”

Drugs for Diabetic Nephropathy- Full Review

“…Decreases hypertrophy of kidney in diabetic mice [74] 6) NF-κB p50 nuclear translocation is decreased [75] 7) PARP-1 Inhibition prevents NF-KB/AP-1 binding at MMP-9 promoter. Hyperglycaemia induced PARP activation plays important role in pathogenesis of glomerulopathy associated with T2DM and could serve as novel therapeutic target.…”

“…1) Tubuloglomerular Sclerosis [75] 2) Podocyte apoptosis 3) Produces fibrosis 4) Increases the production of extracellular matrix…”

“…[95] Drugs that modify TGFβ expression or reduce TGFβ level 1) ACE inhibitor Perindopril reduces intrarenal TGFβ expression and activity [125] 2) ACE inhibitor reduces serum and urinary level of TGFβ [131] 3) Antifibrotic agent N-acetyl-seryl-aspartyl-lysyl-proline reduced extracellular matrix production, prevented fibrosis and albuminuria in mice model. Also additional renoprotection can be offered when combined with angiotensin II receptor antagonist losartan [130,140] www.wjpps.com 2) Several blocking Abs against TGFβ reduce mesangial matrix accumulation and glomerulosclerosis in diabetic mouse model [75,132] 3) TGF-AY1Ab is in clinical development for the treatment of chronic kidney diseases with focus on diabetic nephropathy. [90] DRUGS-Pirfenidone [133] , Tranilast [134,135] , fresolimumab.…”