scholarly journals Prevention of Streptozotocin-Induced Diabetic Nephropathy by MG132: Possible Roles of Nrf2 and IκB

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Lili Kong ◽  
Yangwei Wang ◽  
Manyu Luo ◽  
Yi Tan ◽  
Wenpeng Cui ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Nuclear Factor ◽  
Low Doses ◽  
Wild Type ◽  
Renal Protection ◽  
Proteasomal Activity ◽  
Significant Attenuation ◽  
Proteasomal Inhibitor

Our previous study showed that proteasomal inhibitor MG132 can prevent diabetic nephropathy (DN) along with upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The present study was to investigate whether MG132 can prevent DN in wild-type and Nrf2-KO mice. Type 1 diabetes was induced in wild-type and Nrf2-KO mice by multiple low doses of streptozotocin. Two weeks after streptozotocin injection, both wild-type and Nrf2-KO mice were randomly divided into four groups: control, MG132, DM, and DM/MG132. MG132 (10 μg/kg/day) or vehicle was administered intraperitoneally for 4 months. Renal function, morphology, and biochemical changes were measured after 4-month treatment with MG132. MG132 treatment suppressed proteasomal activity in the two genotypes. In wild-type mice, MG132 attenuated diabetes-induced renal dysfunction, fibrosis, inflammation, and oxidative damage along with increased Nrf2 and IκB expression. Deletion of Nrf2 gene resulted in a partial, but significant attenuation of MG132 renal protection in Nrf2-KO mice compared with wild-type mice. MG132-increased IκB expression was not different between wild-type and Nrf2-KO mice. This work indicates that MG132 inhibits diabetes-increased proteasomal activity, resulting in Nrf2 and IκB upregulation and renal protection, which could be used as a strategy to prevent diabetic nephropathy.

scholarly journals Reduced Pathology following Infection with Transgenic Leishmania major Expressing Murine CD40 Ligand

2007 ◽  
Vol 75 (6) ◽  
pp. 3140-3149 ◽  
Author(s):  
Ann E. Field ◽  
Sagie Wagage ◽  
Sean M. Conrad ◽  
David M. Mosser
Keyword(s):  
Immune Response ◽  
Leishmania Major ◽  
Cd40 Ligand ◽  
High Dose ◽  
Low Doses ◽  
Wild Type ◽  
Safety Concerns ◽  
Transgenic Organisms ◽  
Transgenic Parasites

ABSTRACT Leishmanization is the inoculation of live Leishmania into the host to vaccinate against subsequent infections. This approach has been largely discontinued due to safety concerns. We have previously shown that combining CD40 ligand (CD40L) with Leishmania antigen preferentially induces a type 1 immune response and provides some protection to vaccinated mice (G. Chen, P. A. Darrah, and D. M. Mosser, Infect. Immun. 69:3255-3263, 2001). In the present study, we developed transgenic L. major organisms which express and secrete the extracellular portion of CD40L (L. major CD40LE). We hypothesized that these organisms would be less virulent but more immunogenic than wild-type organisms and therefore be more effective at leishmanization. Transgenic parasites expressing CD40L mRNA and protein were developed. BALB/c mice infected with these parasites developed significantly smaller lesions containing fewer parasites than animals infected with wild-type organisms. Infection of resistant C57BL/6 mice with low doses of transgenic parasites induced a significant amount of protection against subsequent high-dose infection with wild-type organisms. These results demonstrate that transgenic organisms expressing CD40L are less virulent than wild-type organisms while retaining full immunogenicity.

P0973ALLOSTERIC C-C CHEMOKINE RECEPTOR TYPE 2 (CCR2) INHIBITION IMPROVES RENAL FUNCTION IN A MURINE MODEL OF DIABETIC NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Zhenhua Miao ◽  
Linda S Ertl ◽  
Bin Zhao ◽  
Yu Wang ◽  
Dale Newland ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Murine Model ◽  
Albumin Excretion Rate ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Glomerular Injury ◽  
Allosteric Site ◽  
Renal Protection ◽  
Monocyte Migration

Abstract Background and Aims Diabetic nephropathy (DN) is a syndrome characterized by pathological levels of proteinuria, glomerular lesions and reduction in the glomerular filtration rate (GFR) in diabetic patients. Several lines of evidence support a role of CCR2 in the pathogenesis of DN. Recent studies have demonstrated that existing small molecule CCR2 antagonists can be placed in two classes, distinguished by their interaction with one of two distinct binding sites on CCR2: an extracellular site for which antagonists compete directly with native ligands (the orthosteric site), or an intracellular allosteric binding site. To better understand the functional differences between these antagonists we compared an example of each class in a murine model of DN. Our results revealed that the allosteric, but not the orthosteric CCR2 inhibitors ameliorated the proteinuria and improved glomerular histopathology in this model of DN. Method We used db/db mice to model DN. Several structurally distinct CCR2 inhibitors with that bind to either the allosteric (CCR2-RA-[R] and CCX872) or orthosteric (MK-0812 and CCX598) sites were compared. Pharmacokinetic (PK) properties and renal functional parameters were assessed, including trough drug levels and proteinuria (urinary albumin excretion rate UAER; urine albumin creatinine ratio UACR). Histopathology and electron microscopy (EM) were performed to assess any potential tissue-protective effects of the antagonists. Results Both the allosteric inhibitors (CCR2-RA-[R] and CCX872) and the orthosteric inhibitors (MK-0812 and CCX598) were potent CCR2 antagonists with desirable PK in mouse in so far as both classes effectively blocked CCR2-mediated monocyte migration into the peritoneal cavity in the thioglycollate-induced peritonitis model. At comparable drug coverage levels, CCR2-RA-[R] and CCX872 rapidly and significantly reduced UAER/UACR (CCX872: 70 % at day 7 vs vehicle, p<0.0001; and 60 % at day 14 vs vehicle, p=0.001; CCR2-RA-[R]: 60 % at day 7 vs vehicle, p=0.0001; and 58 % at day 14 vs vehicle, p=0.005), but MK-0812 and CCX598 did not exhibit proteinuria lowering effect. Histological parameters including glomerular injury and glomerular basement membrane (GBM) thickness were also improved after CCX872 treatment in db/db mice. Conclusion Allosteric antagonists of CCR2 provide significant and rapid renal protection in the db/db murine model of DN, as evidenced by improvements in renal function and histological parameters, while potent orthosteric CCR2 antagonists were not effective in the model. Our data suggest that targeting the effectiveness of CCR2 antagonists in DN are directly dependent on binding to the allosteric site of CCR2.

scholarly journals Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

2015 ◽  
Vol 112 (18) ◽  
pp. 5815-5820 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Adil M. H. Gasim ◽  
Ruriko Grant ◽  
Albert S. Chang ◽  
Hyung-Suk Kim ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Creatinine Clearance ◽  
Transforming Growth Factor ◽  
Differential Susceptibility ◽  
Basement Membranes ◽  
Genotypic Differences ◽  
Wild Type ◽  
Albumin Excretion

Nephropathy develops in many but not all patients with long-standing type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor β1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2Akita). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes.

PANCREAS TRANSPLANT ALONE IN TYPE 1 DIABETIC RECIPIENTS WITH OVERT DIABETIC NEPHROPATHY: RENAL FUNCTION OUTCOME

2010 ◽  
Vol 90 ◽  
pp. 277
Author(s):  
U. Boggi ◽  
F. Vistoli ◽  
C. Croce ◽  
S. Signori ◽  
C. Moretto ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Pancreas Transplant

scholarly journals Anti-Diabetic Nephropathy Activities of Polysaccharides Obtained from Termitornyces albuminosus via Regulation of NF-κB Signaling in db/db Mice

2019 ◽  
Vol 20 (20) ◽  
pp. 5205 ◽  
Author(s):  
Chang Yang ◽  
Qi Feng ◽  
Huan Liao ◽  
Xinlei Yu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Kinase B ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Nuclear Factor ◽  
Renal Protection ◽  
Glucose Levels ◽  
Edible Fungus ◽  
Cytokine Array ◽  
Anti Inflammatory

Termitornyces albuminosus is a kind of traditional Chinese edible fungus rich in nutrients and medicinal ingredients, and it has anti-oxidative, analgesic and anti-inflammatory effects. However, the hypoglycemic and nephroprotective effects of polysaccharides separated from T. albuminosus (PTA) have not been reported. The properties of PTA were analyzed in a BKS.Cg-Dock7m +/+ Leprdb/JNju (db/db) mouse model of diabetes. After the administration of PTA for eight weeks, the hypoglycemic and hypolipidemic activities of PTA in the db/db mice were assessed. The results of a cytokine array combined with an enzyme-linked immunosorbent assay confirmed the anti-oxidative and anti-inflammatory activities of PTA. An eight-week administration of PTA caused hypoglycemic and hypolipidemic functioning, as indicated by suppressed plasma glucose levels, as well as the modulation of several cytokines related to glycometabolism, in the sera and kidneys of the mice. PTA treatment also had a protective effect on renal function, restoring renal structures and regulating potential indicators of nephropathy. In the kidneys of the db/db mice, PTA treatment reduced the activation of protein kinase B, the inhibitor of κB kinase alpha and beta, and the inhibitor of κB alpha and nuclear factor-κB (NF-κB). We establish the hypoglycemic, hypolipidemic, and anti-diabetic nephropathy effects of PTA, and we find that the renal protection effects of PTA may be related to anti-inflammatory activity via the regulation of NF-κB signaling.

Plasma D Dimer: A Useful Marker of Fibrin Breakdown in Renal Failure

1989 ◽  
Vol 61 (03) ◽  
pp. 522-525 ◽  
Author(s):  
M P Gordge ◽  
R W Faint ◽  
P B Rylance ◽  
H Ireland ◽  
D A Lane ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Monoclonal Antibodies ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Plasma Concentrations ◽  
Significant Negative Correlation ◽  
Healthy Controls ◽  
D Dimer

SummaryD dimer and other large fragments produced during the breakdown of crosslinked fibrin may be measured by enzyme immunoassay using monoclonal antibodies. In 91 patients with renal disease and varying degrees of renal dysfunction, plasma D dimer showed no correlation with renal function, whereas FgE antigen, a fibrinogen derivative which is known to be cleared in part by the kidney, showed a significant negative correlation with creatinine clearance. Plasma concentrations of D dimer were, however, increased in patients with chronic renal failure (244 ± 3l ng/ml) (mean ± SEM) and diabetic nephropathy (308 ± 74 ng/ml), when compared with healthy controls (96 ± 13 ng/ml), and grossly elevated in patients with acute renal failure (2,451 ± 1,007 ng/ml). The results indicate an increase in fibrin formation and lysis, and not simply reduced elimination of D dimer by the kidneys, and are further evidence of activated coagulation in renal disease. D dimer appears to be a useful marker of fibrin breakdown in renal failure.

Urinary Beta-Thromboglobulin Correlates with Impairment of Renal Function in Patients with Diabetic Nephropathy

1986 ◽  
Vol 56 (02) ◽  
pp. 229-231 ◽  
Author(s):  
A H Hopper ◽  
H Tindall ◽  
J A Davies
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Microvascular Disease ◽  
Normal Subjects ◽  
Specific Protein ◽  
Creatinine Concentration ◽  
Β2 Microglobulin ◽  
Plasma Creatinine Concentration ◽  
Insulin Dependent ◽  
Indium 111

SummaryTBeta-thromboglobulin (βTG) is a platelet-specific protein and since its concentration in plasma rises when platelets are activated, it has been used as an indicator of platelet involvement in vascular disease. Since platelets might be involved in the pathogenesis of diabetic microvascular disease we measured urinary βTG in 20 insulin-dependent diabetics with nephropathy and compared the results with those from 20 normal subjects. Measurement of βTG in urine was undertaken to avoid errors induced by blood sampling and to gain information over a prolonged period using a single assay. Measurements were made of βTG, β2-microglobulin and total protein in urine collected for 24 h and creatinine and β2 microglobulin in plasma. Survival of indium-111-labelled platelets was measured in nine patients. Urinary PTG was significantly (p <0.02) increased in the 20 patients compared with 20 normal volunteers (median value 1.3 vs 0.8 μg/24 h). There was a strong correlation between urinary βTG excretion and plasma creatinine concentration (r = 0.8, p <0.0001) and plasma β2-microglobulin concentration (r = 0.9, p <0.0001). Urinary βTG concentration did not correlate with platelet survival. The results indicate that although urinary βTG is significantly increased in patients with diabetic nephropathy its concentration in urine correlates with indicators of glomerular filtration rather than with a test of platelet activation.

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