scholarly journals Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

2011 ◽  
Vol 300 (4) ◽  
pp. F873-F886 ◽  
Author(s):  
Daisuke Saito ◽  
Yohei Maeshima ◽  
Tatsuyo Nasu ◽  
Hiroko Yamasaki ◽  
Katsuyuki Tanabe ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Efficacy ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Protein Levels ◽  
Type 2 Diabetic

The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365–2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-β1, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1+) and desmin+ podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

Therapeutic effects of interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 on diabetic nephropathy in type 2 diabetic mice

2020 ◽  
Vol 393 (7) ◽  
pp. 1197-1209
Author(s):  
Mitsuhiro Kondo ◽  
Atsuo Tahara ◽  
Kazumi Hayashi ◽  
Hiroshi Inami ◽  
Takeshi Ishikawa ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Interleukin 1 ◽  
Therapeutic Effects ◽  
Diabetic Mice ◽  
Type 2 Diabetic

Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes

2021 ◽  
Vol 320 (4) ◽  
pp. F548-F558
Author(s):  
Hyun Soon Lee ◽  
Ji Yeon Suh ◽  
Byeong-Choel Kang ◽  
Eugene Lee
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Fish Oil ◽  
Olive Oil ◽  
Renal Cortex ◽  
Diabetic Mice ◽  
Podocyte Injury ◽  
Type 2 Diabetic

In podocytes, PA rapidly induced immunoproteasome expression but ultimately decreased it, while OA and EPA restored the decreased immunoproteasome levels. In the renal cortex of type 2 diabetic mice, immunoproteasome expression was significantly decreased, whereas feeding of OA-rich olive oil or EPA-rich fish oil diets protected them against the reduced immunoproteasome expression and progression of diabetic nephropathy. Thus, lipotoxicity-induced podocyte injury with impaired immunoproteasome expression may be related to the pathogenesis of diabetic nephropathy.

Mechanisms through which bradykinin promotes glomerular injury in diabetes

2005 ◽  
Vol 288 (3) ◽  
pp. F483-F492 ◽  
Author(s):  
Yan Tan ◽  
Bing Wang ◽  
Joo-Seob Keum ◽  
Ayad A. Jaffa
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Collagen I ◽  
Mrna Levels ◽  
Glomerular Injury ◽  
Western Blots ◽  
Protein Levels

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8 M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.

The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension

2014 ◽  
Vol 307 (3) ◽  
pp. F317-F325 ◽  
Author(s):  
Florian Gembardt ◽  
Christoph Bartaun ◽  
Natalia Jarzebska ◽  
Eric Mayoux ◽  
Vladimir T. Todorov ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Sglt2 Inhibitor ◽  
Western World ◽  
Diabetic Mice ◽  
Antidiabetic Therapy ◽  
Beneficial Effects ◽  
Stage Renal Disease ◽  
Early Features ◽  
Type 2 Diabetic

Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na+-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep<ob>/WiscJ (BTBR ob/ ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ ob mice received 1 μg·kg body wt−1·day−1 ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ ob mice with and without hypertension.

scholarly journals Therapeutic effects of ethanolic extract from the green cocoon shell of silkworm Bombyx mori on type 2 diabetic mice and its hypoglycaemic mechanism

2019 ◽  
Vol 8 (3) ◽  
pp. 407-420 ◽  
Author(s):  
Jin-Ge Zhao ◽  
Hai-Yan Wang ◽  
Zheng-Guo Wei ◽  
Yu-Qing Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Bombyx Mori ◽  
Protein Metabolism ◽  
Complex Disease ◽  
Ethanolic Extract ◽  
Therapeutic Effects ◽  
Diabetic Mice ◽  
Type 2 Diabetic ◽  
Silkworm Bombyx Mori

Diabetes mellitus is a clinically complex disease characterized by hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism.

scholarly journals Chronic Cadmium Exposure Aggravates the Cardiac Dysfunction in Type 2 Diabetic Mice by Promoting Inflammation and Fibrosis

2021 ◽  
Author(s):  
Xiuxiu Liu ◽  
Shuai Wang ◽  
Mengyang Li ◽  
Jiafu Li ◽  
Zhijie Sheng ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Natriuretic Peptide ◽  
Transforming Growth Factor ◽  
Troponin T ◽  
Exposure Level ◽  
Diabetic Mice ◽  
Cd Exposure ◽  
Experimental Group ◽  
Type 2 Diabetic

Abstract Background: Diabetic cardiomyopathy (DCM) is a serious diabetic complication with high mortality. Cadmium (Cd) is a ubiquitous environmental contaminant and plays an important role in cardiac lesions. However, whether Cd aggravates DCM is debatable. In the present study, the effects of chronic Cd exposure on cardiomyopathy in normal and type 2 diabetic mice were investigated. Methods: Sixty male C57BL/6J mice were randomly divided into four groups: blank control (normal mice without Cd exposure), Cd control (normal mice with Cd exposure, exposure level 1.74-2.45 mg/kg/day), diabetic mice control (diabetic mice without Cd exposure) and experimental group (diabetic mice with Cd exposure, exposure level 1.37-3.58 mg/kg/day). After 16 weeks Cd exposure, echocardiography was performed to determine cardiac structure and function. Other outcomes measures included myocardial injury, inflammation and fibrosis. Results: Cd damaged the cardiac function by decreased EF% (ejection fraction) and FS% (fractional shortening) and increased concentration of cTnT (cardiac troponin T) and the expressions of BNP (brain natriuretic peptide) and ANP (atrial natriuretic peptide) in normal mice. For experimental group, the expression of IL-1 (Interleukin-1), TNF-α (tumor necrosis factor-alpha), MCP-1 (monocyte chemotactic protein 1), FN (fibronectin) and TGF-β1 (transforming growth factor-β1) were significantly increased, indicating that Cd promoted the accumulations of fibrosis and inflammation in diabetic mice. In terms of cardiac function, compared with normal mice, the cardiac injury marker of experimental mice was increased and the myocardial contractility was further attenuate, suggesting diabetic mice were more sensitive than normal mice when exposed to cadmium. Conclusion: Cd could damage the heart contractility and aggravate the disruption of cardiac function in diabetic mice by deteriorating inflammation and fibrosis.

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