Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.
ABSTRACT Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.
Article: Changes in glomerular mesangium in kidneys with congenital nephrotic syndrome of the Finnish type.[show abstract] [hide abstract]
ABSTRACT: Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease caused by mutations in a major podocyte protein, nephrin. NPHS1 is associated with heavy proteinuria and the development of glomerular scarring. We studied the cellular and molecular changes affecting the glomerular mesangium in NPHS1 kidneys. Marked hyperplasia of mesangial cells (MC) was mainly responsible for the early mesangial expansion in NPHS1 glomeruli. The levels of the proliferation marker, mindbomb homolog 1 and the major MC mitogen, platelet-derived growth factor, and its receptors, however, were quite normal. Only a small number of cells were positive for CD68 (marker for phagocytic cells) and CD34 (marker for mesenchymal precursor cells) in the NPHS1 mesangium. MCs strongly expressed alpha-smooth muscle actin, indicating myofibloblast transformation. The expression levels of the profibrotic mediators osteopontin and transforming growth factor beta were up-regulated in NPHS1 glomeruli by 3.2 and 1.6-fold, respectively, compared to the controls. The synthesis by MCs of the typical fibroblast products collagen I, fibronectin, and tenascin, however, was low, and the extracellular matrix increase was caused by the accumulation of a normal MC product, collagen IV. The results indicate that severe glomerular sclerosis can develop without major qualitative cellular or molecular changes in the mesangium.Pediatric Nephrology 12/2009; 25(5):867-75. · 2.52 Impact Factor
Article: Body weight control by a high-carbohydrate/low-fat diet slows the progression of diabetic kidney damage in an obese, hypertensive, type 2 diabetic rat model.[show abstract] [hide abstract]
ABSTRACT: Obesity is one of several factors implicated in the genesis of diabetic nephropathy (DN). Obese, hypertensive, type 2 diabetic rats SHR/NDmcr-cp were given, for 12 weeks, either a normal, middle-carbohydrate/middle-fat diet (MC/MF group) or a high-carbohydrate/low-fat diet (HC/LF group). Daily caloric intake was the same in both groups. Nevertheless, the HC/LF group gained less weight. Despite equivalent degrees of hypertension, hyperglycemia, hyperlipidemia, hyperinsulinemia, and even a poorer glycemic control, the HC/LF group had less severe renal histological abnormalities and a reduced intrarenal advanced glycation and oxidative stress. Mediators of the renoprotection, specifically linked to obesity and body weight control, include a reduced renal inflammation and TGF-beta expression, together with an enhanced level of adiponectin. Altogether, these data identify a specific role of body weight control by a high-carbohydrate/low-fat diet in the progression of DN. Body weight control thus impacts on local intrarenal advanced glycation and oxidative stress through inflammation and adiponectin levels.Journal of obesity 01/2010; 2010.
Article: Deletion of platelet-derived growth factor receptor-β improves diabetic nephropathy in Ca²⁺/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice.[show abstract] [hide abstract]
ABSTRACT: The activation of platelet-derived growth factor receptor-β (PDGFR-β) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-β signalling during the development of diabetic nephropathy. We recently generated pancreatic beta cell-specific Ca(2+)/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (CaMKIIα mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-β (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-β gene on diabetic nephropathy in CaMKIIα mice was evaluated at 10 and 16 weeks of age. The plasma glucose concentrations and HbA(1c) levels were elevated in the CaMKIIα mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-β gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKIIα mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-β gene deletion. The activation of PDGFR-β signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKIIα mice.Diabetologia 08/2011; 54(11):2953-62. · 6.81 Impact Factor