scholarly journals Renal Protective Effect of Xiao-Chai-Hu-Tang on Diabetic Nephropathy of Type 1-Diabetic Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Chun-Ching Lin ◽  
Liang-Tzung Lin ◽  
Ming-Hong Yen ◽  
Juei-Tang Cheng ◽  
Chung-Hsi Hsing ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Serum Glucose ◽  
Collagen Iv ◽  
Expression Data ◽  
Diabetic Mice ◽  
Renal Hypertrophy ◽  
Renal Functions ◽  
Vehicle Treatment

Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese medicine formula consisting of seven medicinal plants, is used in the treatment of various diseases. We show here that XCHT could protect type-1 diabetic mice against diabetic nephropathy, using streptozotocin (STZ)-induced diabetic mice and high-glucose (HG)-exposed rat mesangial cell (RMC) as models. Following 4 weeks of oral administration with XCHT, renal functions and renal hypertrophy significantly improved in the STZ-diabetic mice, while serum glucose was only moderately reduced compared to vehicle treatment. Treatment with XCHT in the STZ-diabetic mice and HG-exposed RMC resulted in a decrease in expression levels of TGF-β1, fibronectin, and collagen IV, with concomitant increase in BMP-7 expression. Data from DPPH assay, DHE stain, and CM-H2DCFDA analysis indicated that XCHT could scavenge free radicals and inhibit high-glucose-induced ROS in RMCs. Taken together, these results suggest that treatment with XCHT can improve renal functions in STZ-diabetic mice, an effect that is potentially mediated through decreasing oxidative stress and production of TGF-β1, fibronectin, and collagen IV in the kidney during development of diabetic nephropathy. XCHT, therefore merits further investigation for application to improve renal functions in diabetic disorders.

scholarly journals Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose‐induced oxidative stress in type 1 diabetic mice

2016 ◽  
Vol 4 (4) ◽  
Author(s):  
Takashi Hatanaka ◽  
Daisuke Ogawa ◽  
Hiromi Tachibana ◽  
Jun Eguchi ◽  
Tatsuyuki Inoue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Diabetic Mice

scholarly journals Optimal LDR to Protect the Kidney From Diabetes: Whole-Body Exposure to 25 mGy X-rays Weekly for 8 Weeks Efficiently Attenuates Renal Damage in Diabetic Mice

Dose-Response ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. 155932581878984 ◽  
Author(s):  
Jie Cheng ◽  
Fengsheng Li ◽  
Guanjun Wang ◽  
Weiying Guo ◽  
Shan Huang ◽  
...  
Keyword(s):  
Low Dose ◽  
Collagen Iv ◽  
Whole Body ◽  
Detectable Effect ◽  
X Rays ◽  
Diabetic Mice ◽  
Low Dose Radiation ◽  
Functional Changes ◽  
Renal Expression

To explore an optimal frequency of whole-body low-dose radiation (LDR) to protect the kidney from diabetes, type 1 diabetic mice were induced with multiple injections of low-dose streptozotocin in male C57BL/6J mice. Diabetic or age-matched normal mice received whole-body exposure to 12.5 or 25 mGy either every other day or weekly for 4 or 8 weeks. Diabetes decreased the urinary creatinine and increased the microalbumin in urine, renal accumulation of 3-nitrotyrosine and 4-hydroxynonenal, and renal expression of collagen IV and fibronectin. All these renal pathological and functional changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens. However, whole-body exposure of diabetic mice to 25 mGy weekly and to 12.5 mGy every other day for 8 weeks provided a better prevention of diabetic nephropathy than other LDR regimens. Furthermore, whole-body exposure to 25 mGy weekly for 8 weeks showed no detectable effect on the kidney of normal mice, but whole-body exposure to normal mice at 12.5 mGy every other day for 8 weeks increased urinary microalbumin and renal expression of collagen IV and fibronectin. These results suggest that whole-body exposure to LDR at 25 mGy weekly is the optimal condition of LDR to protect the kidney from diabetes.

scholarly journals High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

2016 ◽  
Vol 113 (8) ◽  
pp. 2218-2222 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Albert S. Chang ◽  
Ruriko Grant ◽  
Hyung-Suk Kim ◽  
Victoria J. Madden ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Lipid Peroxides ◽  
Transforming Growth Factor Β1 ◽  
Genome Wide Association Studies ◽  
Diabetic Mice ◽  
Stage Renal Disease ◽  
End Stage

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.

P0983INHIBITION OF ATF3 BY RAF INHIBITOR GW5074 ON DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jee Young Han ◽  
Jin Joo Cha ◽  
Young Sun Kang ◽  
Jung Yeon Ghee ◽  
Ji Ae Yoo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Kinase Inhibitor ◽  
Protective Role ◽  
Activating Transcription Factor 3 ◽  
Diabetic Mice ◽  
Mice Model ◽  
Gene Expressions

Abstract Background and Aims Activating Transcription Factor 3 (ATF3) is a stress-adaptive transcription factor, which has been suggested to be involved in maintaining glucose homeostasis. ATF3 respond rapidly to various stimuli like high glucose, fatty acids and oxidative stress, and is observed to either protective or detrimental effects in diabetic condition. Therefore to elucidate the exact role in diabetic nephropathy of ATF3, we investigated the role of ATF3 by inhibition with Raf-inhibitor GW5047 on diabetic mice model. Method ATF3 level was examined in the mouse podocytes and NRK cells with either overexpression or downregulation with ATF3. 8 week db/m and db/db mice as the model of diabetic mice were examined for the expression of ATF3 and were treated with GW5074, a Raf1 kinase inhibitor targeting the ATF3 intraperitoneally with a dose of 0.5mg/kg for 12 weeks. Results In cultured mouse podocytes and NRK cells, high glucose and angiotensin II markedly increased ATF3 expression. Gene Expressions of NOX4, MCP-1 and NF-kB were augmented by ATF3, and were attenuated by ATF3 siRNA. In db/db mice, plasma ATF3 level was not different from control db/m, however the urinary ATF3 excretion was significantly higher. Treatment of GW5074 decreased urinary ATF3 excretion. After 12 week treatment, serum creatinine level was significantly lower in the treatment db/db group, with less systemic oxidative stress. There were no significant differences in body weight, whereas the food intake was decreased in GW5047 group. Overall lipid profile or HOMA-IR, HbA1c level was not different from each group. Serum adiponectin were otherwise increased in GW5074 group. Urinary excretion of albumin at 2 month of treatment decreased with urinary nephrin excretion. Trend of increased gene expression of JNK, p-38, smad2, ERK which was downregulated by GW5074 was noted. Conclusion These findings suggest that in diabetic condition, the activation of ATF3 is associated pathogenesis of diabetic nephropathy and targeting ATF3 may have a protective role in the disease progression.

scholarly journals Therapy with antisense TGF-β1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice

2000 ◽  
Vol 278 (4) ◽  
pp. F628-F634 ◽  
Author(s):  
Dong Cheol Han ◽  
Brenda B. Hoffman ◽  
Soon Won Hong ◽  
Jia Guo ◽  
Fuad N. Ziyadeh
Keyword(s):  
Proximal Tubule ◽  
High Glucose ◽  
Leucine Incorporation ◽  
Diabetic Mice ◽  
Renal Hypertrophy ◽  
Kidney Weight ◽  
Cell Hypertrophy ◽  
Proximal Tubular ◽  
Tgf Β1

Inhibition of gene expression by antisense oligodeoxynucleotides (ODNs) relies on their ability to bind complementary mRNA sequences and prevent translation. The proximal tubule is a suitable target for ODN therapy in vivo because circulating ODNs accumulate in the proximal tubule in high concentrations. Because increased proximal tubular transforming growth factor- β1 (TGF-β1) expression may mediate diabetic renal hypertrophy, we investigated the effects of antisense TGF-β1 ODN on the high-glucose-induced proximal tubular epithelial cell hypertrophy in tissue culture and on diabetic renal hypertrophy in vivo. Mouse proximal tubular cells grown in 25 mM d-glucose and exposed to sense ODN as control (1 μM) exhibited increased3[H]leucine incorporation by 120% and total TGF-β1 protein by 50% vs. culture in 5.5 mM d-glucose. Antisense ODN significantly decreased the high-glucose-stimulated TGF-β1 secretion and leucine incorporation. Continuous infusion for 10 days of ODN (100 μg/day) was achieved via osmotic minipumps in diabetic and nondiabetic mice. Sense ODN-treated streptozotocin-diabetic mice had 15.3% increase in kidney weight, 70% increase in α1(IV) collagen and 46% increase in fibronectin mRNA levels compared with nondiabetic mice. Treatment of diabetic mice with antisense ODN partially but significantly decreased kidney TGF-β1 protein levels and attenuated the increase in kidney weight and the α1(IV) collagen and fibronectin mRNAs. In conclusion, therapy with antisense TGF-β1 ODN decreases TGF-β1 production and attenuates high-glucose-induced proximal tubular cell hypertrophy in vitro and partially prevents the increase in kidney weight and extracellular matrix expression in diabetic mice.

scholarly journals SO026HUMAN KIDNEY PROXIMAL TUBULAR 3D SPHEROIDS TO STUDY THE ROLE OF ADAM17 IN DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Vanesa Palau ◽  
Bramasta Nugraha ◽  
Maximilian Emmert ◽  
Simon Hoerstrup ◽  
Julio Pascual Santos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Human Kidney ◽  
Collagen Iv ◽  
Control Group ◽  
Wild Type ◽  
Factor Α ◽  
3D Spheroids

Abstract Background and Aims ADAM17 is a disintegrin and metalloproteinase initially described to cleave the tumor necrosis factor α (TNFα). Currently, it is known that it can also release ectodomains of a diverse variety of molecules such as, transforming growth factor α (TGFα), L-selectin, and angiotensin-converting enzyme 2 (ACE2). It has been shown that ADAM17 protein expression increases in kidney mesangial cells after incubation with high glucose media mimicking what has been observed in diabetic patients and experimental models of diabetic nephropathy. We now studied the effect ADAM17 deletion on human kidney cells (HKC-8) in a 3D spheroids in vitro cell culture incubated with high glucose, low glucose and mannitol medium resembling the in vivo human kidney diabetic environment. Method ADAM17 deletion was performed using the CRISPR/Cas9 technology. HKC8 cells grew inside a RGD-functionalized dextran hydrogel to obtain 3D spheroids. 13 days post-seeding, the spheroids were incubated with 35mM of D-glucose (HG), 5mM of D-glucose (LG) or 35mM of mannitol as osmotic control for 6h, 24h or 72h. The quality of the established 3D cell culture of mature HKC-8 spheroids was assessed by Aquoporin-1 and Glut-1 staining. After incubations quantitative-PCR analyses were performed for fibrotic and inflammatory markers. Immunofluorescence for fibrotic markers was performed on HKC-8 spheroids incubated for 72h. Results High glucose (HG) medium induced CCL5 gene expression on wild-type HKC-8 spheroids after 6h and 24h of incubation in comparison with the control group. Interestingly, in the ADAM17-deleted spheroids, CCL5 gene expression maintained similar to control after 6h of incubation with HG medium and tended to decrease after 24h of incubation in comparison with the wild-type. Collagen IV gene expression was increased in the wild-type spheroids incubated with HG in comparison with the control group. In ADAM17-deleted spheroids, Collagen IV gene expression was significantly decreased in the cells incubated with HG in comparison with the wild-type cells incubated with HG. HG increased the expression of α-SMA, fibronectin and Collagen IV in wild-type spheroids. Adam17 deletion blocked the increase of α-SMA, fibronectin and Collagen IV expression compared with wild-type cells after 72h of incubation. Conclusion ADAM17 blockade protects against fibrosis and inflammation in human kidney tubular spheroids under high glucose.

Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury

2007 ◽  
Vol 293 (5) ◽  
pp. F1727-F1735 ◽  
Author(s):  
Shu Liu ◽  
Lihua Shi ◽  
Shuxia Wang
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Urinary Albumin Excretion ◽  
Urinary Albumin ◽  
Glomerular Hypertrophy ◽  
Upstream Stimulatory Factor ◽  
Diabetes Onset ◽  
Stimulatory Factor

Diabetic nephropathy is the most common cause of end-stage renal failure in the United States. Hyperglycemia is an important factor in the pathogenesis of diabetic nephropathy. Hyperglycemia upregulates the expression of transforming growth factor-β (TGF-β), which stimulates extracellular matrix deposition in the kidney, contributing to the development of diabetic nephropathy. Our previous studies demonstrated that the transcription factor, upstream stimulatory factor 2 (USF2), was upregulated by high glucose, which bound to an 18-bp sequence in the thrombospondin 1 (TSP1) gene promoter and regulated high glucose-induced TSP1 expression and TGF-β activity in mesangial cells, suggesting that USF2 might play a role in the development of diabetic nephropathy. In the present studies, we examined the effect of overexpression of USF2 on the development of diabetic nephropathy. Type 1 diabetes was induced in USF2 transgenic mice [USF2 (Tg)] and their wild-type littermates (WT) by injection of streptozotocin. Four groups of mice were studied: control WT, control USF2 (Tg), diabetic WT, and diabetic USF2 (Tg). Mice were killed after 15 wk of diabetes onset. At the end of studies, control USF2 (Tg) mice (∼6 mo old) exhibited increased urinary albumin excretion. These mice also exhibited glomerular hypertrophy, accompanied by increased TSP1, active TGF-β, fibronectin accumulation in the glomeruli compared with control WT littermates. Type 1 diabetes onset further augmented the urinary albumin excretion and glomerular hypertrophy in the USF2 (Tg) mice. These findings suggest that overexpression of USF2 accelerates the development of diabetic nephropathy.

scholarly journals Proteasome Activators, PA28α and PA28β, Govern Development of Microvascular Injury in Diabetic Nephropathy and Retinopathy

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Saeed Yadranji Aghdam ◽  
Ali Mahmoudpour
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Diabetic Mice ◽  
Double Knockout ◽  
Monocyte Chemoattractant Protein 1 ◽  
Microvascular Injury ◽  
Retinal Pericytes ◽  
Diabetes Model

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are major complications of type 1 and type 2 diabetes. DN and DR are mainly caused by injury to the perivascular supporting cells, the mesangial cells within the glomerulus, and the pericytes in the retina. The genes and molecular mechanisms predisposing retinal and glomerular pericytes to diabetic injury are poorly characterized. In this study, the genetic deletion of proteasome activator genes, PA28α and PA28β genes, protected the diabetic mice in the experimental STZ-induced diabetes model against renal injury and retinal microvascular injury and prolonged their survival compared with wild type STZ diabetic mice. The improved wellbeing and reduced renal damage was associated with diminished expression of Osteopontin (OPN) and Monocyte Chemoattractant Protein-1 (MCP-1) in the glomeruli of STZ-injected PA28α/PA28β double knockout (Pa28αβDKO) mice and also in cultured mesangial cells and retinal pericytes isolated from Pa28αβDKO mice that were grown in high glucose. The mesangial PA28-mediated expression of OPN under high glucose conditions was suppressed by peptides capable of inhibiting the binding of PA28 to the 20S proteasome. Collectively, our findings demonstrate that diabetic hyperglycemia promotes PA28-mediated alteration of proteasome activity in vulnerable perivascular cells resulting in microvascular injury and development of DN and DR.

scholarly journals ADAMTS13/VWF Axis Potentially Contributes to Diabetic Nephropathy By Regulating PAI-1 Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2240-2240
Author(s):  
Nirav Dhanesha ◽  
Anil K. Chauhan
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Weight Ratio ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Renal Hypertrophy ◽  
Protein Levels ◽  
Pai 1

Abstract Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in hemostasis and thrombosis. Severe deficiency or very low levels of ADAMTS13 in presence of external stimuli results in accumulation of thrombogenic ultra large VWF multimers (which are released from activated endothelium) known to trigger thrombotic microangiopathy. Activated endothelium/dysfunction is a prominent feature of diabetic nephropathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy. Significantly reduced ADAMTS13 and increased plasma VWF levels have been found in diabetic patients with nephropathy. Although major site of ADAMTS13 synthesis is liver, ADAMTS13 is also expressed by podocytes in normal renal cortex. It remains unknown, however, whether VWF and ADAMTS13 imbalance plays a causal role in development of nephropathy in diabetic patients or rather is simply an associate marker of disease status, possibly secondary to endothelial function. We performed experiments in genetic models to determine whether ADAMTS13 and VWF axis contributes to diabetic nephropathy. Methods : Male, 8-10 weeks old wild-type (WT), Adamts13-/- and Vwf-/- mice were made diabetic by injecting multiple low doses of streptozotocin (60 mg/kg, i.p. for five consecutive days). Successful diabetes induction was tested after 2 weeks by measuring blood glucose. Mice having blood glucose levels above 300 mg/dL were included in the study. Controls were nondiabetic littermate mice treated with citrate buffer. The extent of renal injury was evaluated after 28 weeks of diabetes induction by measuring albuminuria and kidney to body weight ratio. Renal hypertrophy and extracellular matrix deposition was quantified by hematoxylin and immunostaining. PAI-1 mRNA and protein levels were measured by real time quantitative RT-PCR and ELISA. Results: Adamts13- /- diabetic mice exhibited significantly increased kidney to body weight ratio (P<0.05 vs. WT diabetic mice). Urine albuminuria, an index of renal injury was significantly elevated in Adamts13-/- diabetic mice (P<0.05 vs. WT diabetic mice). Increased renal injury in Adamts13-/- diabetic mice was concomitant with increased renal hypertrophy and extracellular matrix (ECM) deposition within glomeruli (P<0.05 vs. WT diabetic mice). Murine studies have shown that PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and ECM deposition. A positive association exists between increased PAI-1 levels in glomeruli and microangiopathy in patients with diabetic nephropathy. We determined whether ADAMTS13 deficiency-induced microangiopathy in glomeruli increases PAI-1 levels. Adamts13-/- diabetic mice exhibited increased PAI-1 mRNA and protein levels (P<0.05 vs. WT diabetic mice). VWF remains the only known substrate of ADAMTS13 and increased plasma VWF levels have been associated with diabetic nephropathy. We determined the role of VWF in diabetic nephropathy. Vwf-/- diabetic mice exhibited significantly decreased kidney weight/body weight ratio, less urinary albuminuria, decreased kidney PAI-1 expression levels concomitant with improved kidney morphological changes (P<0.05 vs. WT diabetic mice). Conclusion : These findings provide experimental evidence for the first time that ADAMTS13/VWF axis potentially contributes to diabetic nephropathy, most likely by regulating PAI-1 levels. Disclosures No relevant conflicts of interest to declare.

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