scholarly journals Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney

2001 ◽  
Vol 170 (3) ◽  
pp. 647-651 ◽  
Author(s):  
C Hill ◽  
A Flyvbjerg ◽  
R Rasch ◽  
M Bak ◽  
A Logan
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Western Blotting ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Human Monoclonal Antibody ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Diabetic Kidney ◽  
In The Diabetic Kidney

Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.

scholarly journals Streptozocin Diabetes Elevates all Isoforms of TGF-β in the Rat Kidney

2001 ◽  
Vol 2 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Pascale H. Lane ◽  
Dustin M. Snelling ◽  
William J. Langer
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Fold Increase ◽  
Diabetic Rat ◽  
The Impact ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) is a major promoter of diabetic nephropathy. While TGF-β1 is the most abundaft renal isoform, types 2 and 3 are present as well and have identicalin vitroeffects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-β1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-β2 mRNA increased approximately 6% while its protein doubled. TGF-β-message increased by 25%, producing a 35% increase in its protein. TGF-β- inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-β are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.

Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats

2015 ◽  
Vol 309 (3) ◽  
pp. F227-F234 ◽  
Author(s):  
Julie O'Neill ◽  
Angelica Fasching ◽  
Liselotte Pihl ◽  
Daniela Patinha ◽  
Stephanie Franzén ◽  
...  
Keyword(s):  
Renal Cortex ◽  
Early Stage ◽  
Rat Kidney ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
Diabetic Kidney ◽  
Excretory Function ◽  
In The Diabetic Kidney

Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na+-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na+ transport efficiency [tubular Na+ transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na+ reabsorption suggests the redistribution of active Na+ transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia.

scholarly journals Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney

2010 ◽  
Vol 298 (2) ◽  
pp. F416-F420 ◽  
Author(s):  
Fredrik Palm ◽  
Angelica Fasching ◽  
Peter Hansell ◽  
Örjan Källskog
Keyword(s):  
Nitric Oxide ◽  
Rat Kidney ◽  
Diabetic Rats ◽  
Electrolyte Transport ◽  
Diabetic Rat ◽  
Oxygen Utilization ◽  
Diabetic Kidney ◽  
Transport Efficiency ◽  
In The Diabetic Kidney

Nitric oxide (NO) is a potent regulator of both vascular tone and cellular oxygen consumption (Qo2). Diabetic kidneys have reduced NO availability and increased Qo2. However, the exact nitric oxide synthase (NOS) isoform regulating Qo2, hemodynamics, and excretory function in the diabetic kidney remains unclear. We therefore investigated the effects of both selective neuronal NOS (NOS1) inhibition and nonselective NOS inhibition. Oxygen utilization, electrolyte transport efficiency [tubular Na+ transport (TNa)/Qo2], renal blood flow (RBF), glomerular filtration rate (GFR), and mean arterial pressure (MAP) were measured in vivo in control and streptozotocin-diabetic rats before and after administration of the selective NOS1 inhibitor S-methyl-l-thiocitrulline (SMTC) or the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME). Diabetic rats had higher baseline Qo2 and GFR than control rats, although RBF was similar in the groups. SMTC and l-NAME increased Qo2 and reduced TNa/Qo2 only in the diabetic animals, whereas both inhibitors increased MAP and reduced RBF in both groups. GFR was reduced by l-NAME, but SMTC had no effect in either group. Carbachol increased RBF and decreased MAP in SMTC-treated rats, whereas it had no effect in l-NAME-treated rats, indicating that SMTC selectively inhibited NOS1. In conclusion, NO regulates RBF and GFR similarly in both control and diabetic rats. However, selective NOS1 inhibition increased Qo2 and reduced TNa/Qo2 in the diabetic rat kidney, indicating a pivotal role of NO produced by NOS1 in maintaining control of Qo2 and tissue oxygenation in these kidneys.

scholarly journals Protective Effects of Luteolin on Diabetic Nephropathy in STZ-Induced Diabetic Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Guo Guang Wang ◽  
Xiao Hua Lu ◽  
Wei Li ◽  
Xue Zhao ◽  
Cui Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Antioxidant Properties ◽  
Diabetic Rats ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Sod Activity ◽  
Matrix Expression

Diabetic nephropathy is a long-term complication of diabetic mellitus. Many experimental evidences suggest that persistent hyperglycaemia generates intracellular reactive oxygen species (ROS) and upregulates transforming growth factor-b1 and extracellular matrix expression in mesangial and tubular epithelial cells, which is involved of free radicals in the pathogenesis of diabetes and more importantly in the development of diabetic complications. Antioxidants effectively inhibit high-glucose- and H2O2-induced transforming growth factor-b1 and fibronectin upregulation, thus providing evidence that ROS play an important role in high glucose-induced renal injury. The flavonoid luteolin has been shown to possess direct antioxidant activity, therefore we hypothesize that it may be useful in treatment of many chronic disease associated with oxidative stress, such as diabetic nephropathy via its antioxidant properties. Our results suggested that protection against development of diabetic nephropathy by luteolin treatment involved changes in superoxide dismutase (SOD) activity, the malondialdehyde (MDA) content and expression of Heme Oxygenase-1 (HO-1) protein.

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

2007 ◽  
Vol 292 (4) ◽  
pp. F1141-F1150 ◽  
Author(s):  
Sakiko Ohga ◽  
Kenichi Shikata ◽  
Kosuke Yozai ◽  
Shinichi Okada ◽  
Daisuke Ogawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Diabetic Rats ◽  
Pyrrolidine Dithiocarbamate ◽  
Sprague Dawley ◽  
Diabetic Kidney ◽  
Ppar Γ ◽  
Glomerular Endothelial Cells ◽  
Anti Inflammatory ◽  
In The Diabetic Kidney

Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ), 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)-β, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-κB activity was increased in diabetic rats and reduced by pioglitazone. PPAR-γ 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-κB in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-κB. However, pioglitazone did not show the changes in the presence of PPAR-γ antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

scholarly journals P0966PLACENTAL GROWTH FACTOR DEFICIENCY AGGRAVATES DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ji Hee Lim ◽  
Yaeni Kim ◽  
Eun Nim Kim ◽  
YONGJIE JIN ◽  
Hyung Duk Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Fasting Blood Glucose ◽  
Transforming Growth Factor Β1 ◽  
Cholesterol Concentration ◽  
Glomerular Sclerosis ◽  
Diabetic Kidney ◽  
Mesangial Area

Abstract Background and Aims Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. PlGF exerts favorable angiogenetic and lymphangiogenic activity by binding to VEGF-R1 and -R3, respectively. Due to its functional synergy with VEGF-A, it is required for a correct neovascularization during pathological conditions while inactivation of PlGF contributes to decrease of pathological angiogenesis. Because reduced angiogenesis and lymphagiogenesis that contribute to defective lipid drainage are implicated in the progression diabetic kidney disease, we investigated the role of PlGF in the development of diabetic nephropathy by using PlGF-knockout mice. Method Diabetes was induced by a low-dose streptozotocin injection in 9-week-old male C57BL/6J PlGF-KO and wild-type mice and biochemical and morphological parameters were examined at 12 weeks later. Results In diabetic PlGF-KO mice, fasting blood glucose and HbA1c levels increased significantly and the development of glomerular sclerosis and mesangial area expansion were accompanied by albuminuria. Diabetic PlGF-KO mice exhibited increased expression of type IV collagen, transforming growth factor-β1 and glomerular IHC staining for nephrin, PECAM-1 and WT-1-positive cells and VEGF-R1,-R2,-R3 expression decreased, suggesting decreased endothelial cell and podocyte structure. Intrarenal expression of pLKB1, and pAMPK decreased and that of PPARα, PGC1α, ERRα, p-eNOS, and urinary Nox concentration decreased while iNOS increased, indicating disturbed lipid metabolism and endothelial dysfunction in the same group. Increased intrarenal FFA, TG, and cholesterol concentration represents presence of lipid accumulation. F4/80- and TUNEL-positive cells increased, suggesting increased inflammatory cell infiltration and apoptosis. CD68 and arginase-II increased indicating that macrophage subtype M1 polarization is involved in the inflammatory process. Expression of Bcl2/bax decreased and that of SOD1 and 2 decreased, indicating increased apoptosis and oxidative stress, respectively. Increased expression of intrarenal 8-OHdG and urinary isoprostane level indicates increased oxidative stress. Conclusion Impaired angiogenesis and lymphangiogenesis are implicated in PlGF deficiency and this promotes lipotoxicity-induced inflammation, oxidative stress and deteriorates renal functional and phenotypic parameters in the diabetic kidney.

scholarly journals Fenugreek Prevents the Development of STZ-Induced Diabetic Nephropathy in a Rat Model of Diabetes

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yingli Jin ◽  
Yan Shi ◽  
Yinggang Zou ◽  
Chunsheng Miao ◽  
Bo Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Diabetic Rat ◽  
Dimethyl Formamide ◽  
Interventional Treatment ◽  
Morphological Alterations

The present study aims to examine the protective effect of fenugreek and the underlying mechanism against the development of diabetic nephropathy (DN) in streptozotocin- (STZ-) induced diabetic rats. A rat model of diabetes was successfully established by direct injection of STZ and then the rats were administered an interventional treatment of fenugreek. Parameters of renal function, including blood glucose, albuminuria, hemoglobin A1c (HbA1c), dimethyl formamide (DMF), blood urine nitrogen (BUN), serum creatinine (Scr), and kidney index (KI), were detected in the three groups (Con, DN, and DF). Oxidative stress was determined by the activity of antioxidase. Extracellular matrix (ECM) accumulation and other morphological alterations were evaluated by means of immunohistochemistry and electron microscope. Quantitive (q)PCR was employed to detect the mRNA expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) and protein expression was determined with western blot analysis. DN rats in the present study demonstrated a significant renal dysfunction, ECM accumulation, pathological alteration, and oxidative stress, while the symptoms were evidently reduced by fenugreek treatment. Furthermore, the upregulation of TGF-β1 and CTGF at a transcriptional and translational level in DN rats was distinctly inhibited by fenugreek. Consequently, fenugreek prevents DN development in a STZ-induced diabetic rat model.

scholarly journals Qishen Yiqi Dripping Pill Protects Against Diabetic Nephropathy by Inhibiting the Wnt/β-Catenin and Transforming Growth Factor-β/Smad Signaling Pathways in Rats

2021 ◽  
Vol 11 ◽  
Author(s):  
Qian Zhang ◽  
Xinhua Xiao ◽  
Jia Zheng ◽  
Ming Li ◽  
Miao Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Serum Creatinine ◽  
Signaling Pathways ◽  
Blood Urea Nitrogen ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Diabetic Rats ◽  
Urinary Albumin ◽  
Urea Nitrogen

Diabetic nephropathy is a severe microvascular complication of diabetes. Qishen Yiqi dripping pill (QYDP) has been reported to be a renal protective drug. However, the mechanisms remain unclear. This study was performed to investigate the mechanisms. In this study, Sprague-Dawley rats were injected with streptozotocin to generate a diabetes model. Diabetic rats were administered 150 or 300 mg/kg/day QYDP. After 8 weeks of treatment, serum creatinine, serum blood urea nitrogen, and 24-h urinary albumin were measured. Kidney histological staining and immunostaining were analyzed. Then, the renal tissue was analyzed with a genome expression array. The results showed that QYDP treatment reduced serum creatinine, blood urea nitrogen, and 24-h urinary albumin and improved kidney histology and fibrosis. The gene array revealed that the expression of 189 genes was increased, and that of 127 genes was decreased in the high dosage QYDP group compared with the diabetic group. Pathway and gene ontology analyses showed that the differentially expressed genes were involved in the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2 signaling pathways. QYDP reduced the renal Wnt1, catenin β1, Tgfb1, and Smad2 gene expression and β-catenin, TGF-β, Smad2, collagen I, α-smooth muscle actin, and fibronectin protein expression in diabetic rats. Our results provide the first evidence that QYDP performs its renal-protective function by inhibiting the Wnt/β-catenin and TGF-β/Smad2 signaling pathways in diabetic rats.

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