scholarly journals Impaired Albumin Uptake and Processing Promote Albuminuria in OVE26 Diabetic Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Y. S. Long ◽  
S. Zheng ◽  
P. M. Kralik ◽  
F. W. Benz ◽  
P. N. Epstein
Keyword(s):  
Fold Increase ◽  
Diabetic Mouse ◽  
Proximal Tubules ◽  
Tunel Staining ◽  
Diabetic Mice ◽  
Contributing Factors ◽  
Tubule Cell ◽  
Prolonged Retention ◽  
Normal Urine ◽  
Fluorescent Dextran

The importance of proximal tubules dysfunction to diabetic albuminuria is uncertain. OVE26 mice have the most severe albuminuria of all diabetic mouse models but it is not known if impaired tubule uptake and processing are contributing factors. In the current study fluorescent albumin was used to follow the fate of albumin in OVE26 and normal mice. Compared to normal urine, OVE26 urine contained at least 23 times more intact fluorescent albumin but only 3-fold more 70 kD fluorescent dextran. This indicated that a function other than size selective glomerular sieving contributed to OVE26 albuminuria. Imaging of albumin was similar in normal and diabetic tubules for 3 hrs after injection. However 3 days after injection a subset of OVE26 tubules retained strong albumin fluorescence, which was never observed in normal mice. OVE26 tubules with prolonged retention of injected albumin lost the capacity to take up albumin and there was a significant correlation between tubules unable to eliminate fluorescent albumin and total albuminuria. TUNEL staining revealed a 76-fold increase in cell death in OVE26 tubules that retained fluorescent albumin. These results indicate that failure to process and dispose of internalized albumin leads to impaired albumin uptake, increased albuminuria, and tubule cell apoptosis.

A mitochondria-targeted near-infrared fluorescent probe for imaging viscosity in living cells and a diabetic mice model

2021 ◽  
Author(s):  
Bochao Chen ◽  
Shumei Mao ◽  
Yanyan Sun ◽  
Liyuan Sun ◽  
Ning Ding ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fluorescent Probe ◽  
Near Infrared ◽  
Diabetic Mouse ◽  
Living Cells ◽  
Pancreatic Tissue ◽  
Diabetic Mice ◽  
Mice Model ◽  
Viscosity Changes

A mitochondria-targeted near-infrared fluorescent probe NIR-V with 700 nm emission was designed to monitor cell viscosity changes, which was applied to detect the intracellular viscosity and imagine pancreatic tissue in diabetic mouse model.

scholarly journals Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

2018 ◽  
Author(s):  
Sang-Min Oh ◽  
Jin-Su Shin ◽  
Il-Koo Kim ◽  
Jae-Seung Moon ◽  
Jung-Ho Kim ◽  
...  
Keyword(s):  
Bone Formation ◽  
Rna Sequencing ◽  
Normal Mouse ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Differentially Expressed ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Hypoxia Inducible Factor 1Α

AbstractPatients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1α gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1α gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1α target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1α were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1α via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

scholarly journals Induction of leukocyte adhesion molecules and renal physiologically active molecules in Porphyromonas gingivalis lipopolysaccharide-induced diabetic nephropathy

2020 ◽  
Author(s):  
Koichiro Kajiwara ◽  
Yoshihiko Sawa ◽  
Takahiro Fujita ◽  
Sachio Tamaoki
Keyword(s):  
Diabetic Nephropathy ◽  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Diabetic Mouse ◽  
Renal Parenchyma ◽  
Periodontal Pathogen ◽  
Diabetic Patients ◽  
Renal Tubules ◽  
Diabetic Mice ◽  
Leukocyte Adhesion Molecules

Abstract Background We recently reported that the glomerular endothelium expresses toll-like receptor (TLR)2 and TLR4 in diabetic environments and established that the TLR2 ligand Porphyromonas (P.) gingivalis lipopolysaccharides (LPS) induces nephropathy in diabetic mice. It is thought that P. gingivalis LPS promotes the chronic inflammation with the overexpression of leukocyte adhesion molecules and renal-specific metabolic enzymes by the recognition of P. gingivalis LPS via TLR in the diabetic kidneys. The present study aims to examine the expression of leukocyte adhesion molecules and renal metabolic factors in mouse kidneys with periodontal pathogen P. gingivalis LPS-induced diabetic nephropathy that was recently established. Methods The immunohistochemical investigation was performed on mouse kidney with P. gingivalis LPS-induced diabetic nephropathy model with glomerulosclerosis in glomeruli. Results There were no vessels which expressed vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or fibroblast growth factor (FGF) 23 in diabetic mice, or in healthy mice administered P. gingivalis LPS. However, in diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy the expression of VCAM-1 and the accumulation of FGF23 were established in renal tubules and glomeruli, and the expression of E-selectin was established in renal parenchyma and glomeruli. The angiotensin-converting enzyme 2 (ACE2) was detected in the proximal tubules but not in other regions including not in distal tubules of diabetic mice without LPS, and not in healthy mice administered P. gingivalis LPS. In diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy ACE2 was detected both in renal tubules as well as in glomeruli. The macrophage-1 (Mac-1) and podoplanin-positive cells increased in the renal parenchyma with diabetic condition and there was accumulation in P. gingivalis LPS-induced diabetic nephropathy. As the expression of VCAM-1 and E-selectin is upregulated in glomeruli, tubules, and intertubular capillaries, it is thought that the inflammatory infiltration of the monocyte-macrophage lineage promoted in kidneys with P. gingivalis LPS-induced the diabetic nephropathy. Conclusions P. gingivalis LPS may progressively accelerate the development of the renal inflammatory environment in LPS-accumulated glomeruli with the macrophage infiltration via the renal expression of VCAM-1 and E-selectin, and with ACE2 overexpression and FGF23 accumulation. Periodontitis may be a critical factor in the progress of nephropathy in diabetic patients.

Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

2018 ◽  
Vol 52 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Sisse A Nørgaard ◽  
Fredrik W Sand ◽  
Dorte B Sørensen ◽  
Klas SP Abelson ◽  
Henrik Søndergaard
Keyword(s):  
Weight Loss ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Reduce Weight Loss ◽  
Normal Chow ◽  
Corticosterone Metabolites ◽  
Reducing Stress ◽  
Humane Endpoint

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

Abstract P125: A Novel Role for Survivin in Insulin-induced Inhibition of Myocardial Apoptosis in Ischemic/reperfused Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Rui Si ◽  
Qiujun Yu ◽  
Ning Zhou ◽  
Ling Tao ◽  
Wenyi Guo ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Survivin Expression ◽  
Fold Increase ◽  
Tunel Staining ◽  
Sprague Dawley ◽  
Signaling Mechanism ◽  
Akt Phosphorylation ◽  
Apoptotic Effect

Objectives: Insulin reduces post-ischemic myocardial apoptotic death, but the mechanism remains unclear. Survivin, an anti-apoptotic protein has recently found participating in vascular repair. This study aimed to test the hypothesis that the up-regulation of survivin by insulin may play a role in the antiapoptotic and cardioprotective effects in the ischemic/reperfused (I/R) heart, and further investigate the signaling mechanism involved. Methods : Isolated adult Sprague-Dawley rat hearts were subjected to 30 min regional ischemia and 3 h of reperfusion. The hearts were randomized to receive insulin, insulin plus LY294002 (specific inhibitor of PI3K), or insulin plus rapamycin (specific inhibitor of mTOR) at the start of reperfusion. To further confirm the correlation between survivin and myocardial survival in vitro, cardiomyocytes were infected with adenovirus encoding survivin or transfected with siRNA targeting survivin. Phosphorylation of Akt, mTOR, p70S6K and the expression of protein survivin were determined and infarct size was assessed using TTC staining, cardiomyocytes apoptosis were evaluated after reperfusion by TUNEL staining and DNA laddering. Results: I/R increased myocardial survivin expression. Insulin reperfusion (10 −7 mol/L) resulted in a 4.2-fold increase in survivin expression (P<0.01 vs. I/R alone), which was almost completely blocked by LY294002. Both of the mTOR phosphorylation and survivin expression were inhibited in the group of insulin reperfusion plus LY294002. Rapamycin reperfusion did not change Akt phosphorylation but partially inhibited survivin expression (16.7±1.2 vs. 9.8±1.6, P<0.01 vs. I/R+Ins), which indicated a cardioprotective effect of survivin and a possible PI3K/Akt/mTOR/SVV signaling pathway during I/R. Moreover, over-expressed survivin provides protection against stimulated ischemia reperfusion induced cardiomyocyte apoptosis, while targeting survivin blunted the anti-apoptotic effect of insulin. Conclusion: This study demonstrates that insulin up-regulates myocardial survivin expression, partly at least, via PI3-kinase-mTOR mechanism, which contributes to the anti-apoptotic effect of insulin in the I/R heart.

Dissociation of ammoniagenic enzyme adaptation in rat S1 proximal tubules and ammonium excretion response

1994 ◽  
Vol 267 (3) ◽  
pp. F407-F414 ◽  
Author(s):  
S. R. DiGiovanni ◽  
K. M. Madsen ◽  
A. D. Luther ◽  
M. A. Knepper
Keyword(s):  
Fold Increase ◽  
Proximal Tubules ◽  
Ammonium Excretion ◽  
Production Rates ◽  
Ammonium Production ◽  
Enzyme Adaptation ◽  
Acid Loading ◽  
Microdissected Tubules

We measured ammonium production rates, phosphate-dependent glutaminase (PDG) activity, and glutamate dehydrogenase (GDH) activity in microdissected S1 proximal tubules of rats to investigate the role of adaptations of PDG activity and GDH activity in response to a step increase in acid intake. In vivo ammonium excretion increased much more rapidly than did single-tubule ammonium production in vitro or ammoniagenic enzyme activities measured in microdissected tubules, manifesting an 85-fold increase in the first 24 h. In vitro ammonium production rates in microdissected tubules rose only twofold in the first 24 h, fourfold by day 2, and fivefold by day 4 of acid loading. The adaptation of PDG activity paralleled the increase in single-tubule ammoniagenic capacity measured in vitro. GDH activity, on the other hand, did not change significantly even after 4 days of acid loading. From these observations, we conclude that 1) the adaptation of in vitro ammoniagenic capacity in S1 proximal tubules is temporally associated with an adaptation in PDG activity and not GDH activity, and 2) a major portion of the increased ammonium excretion seen in the first 24 h is due to factors other than an adaptive increase in ammoniagenic enzyme activity.

scholarly journals Quetiapine Attenuates the Neuroinflammation and Executive Function Deficit in Streptozotocin-Induced Diabetic Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Kexin Wang ◽  
Feng Song ◽  
Hongxing Wang ◽  
Jun-hui Wang ◽  
Yu Sun
Keyword(s):  
Cognitive Deficit ◽  
Neuroprotective Effect ◽  
Underlying Mechanism ◽  
Diabetic Mouse ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Protein Loss ◽  
Monocyte Chemoattractant Protein 1 ◽  
Beneficial Effects ◽  
Increased Risk

Diabetic patients are at increased risk for developing memory and cognitive deficit. Prior studies indicate that neuroinflammation might be one important underlying mechanism responsible for this deficit. Quetiapine (QTP) reportedly exerts a significant neuroprotective effect in animal and human studies. Here, we investigated whether QTP could prevent memory deterioration and cognitive impairment in a streptozotocin- (STZ-) induced diabetic mouse model. In this study, we found that STZ significantly compromised the behavioral performance of mice in a puzzle box test, but administering QTP effectively attenuated this behavioral deficit. Moreover, our results showed that QTP could significantly inhibit the activation of astrocytes and microglia in these diabetic mice and reduce the generation and release of two cytokines, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). Meanwhile, QTP also prevented the protein loss of the synaptic protein synaptophysin (SYP) and myelin basic protein (MBP). Here, our results indicate that QTP could inhibit neuroinflammatory response from glial cells and block the injury of released cytokines to neurons and oligodendrocytes in diabetic mice (DM). These beneficial effects could protect diabetic mice from the memory and cognitive deficit. QTP may be a potential treatment compound to handle the memory and cognitive dysfunction in diabetic patients.

scholarly journals Cardiomyopathy in Offspring of Pregestational Diabetic Mouse Pregnancy

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Daniel Dowling ◽  
Niamh Corrigan ◽  
Stephen Horgan ◽  
Chris J. Watson ◽  
John Baugh ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Diabetic Mouse ◽  
Late Gestation ◽  
Collagen Deposition ◽  
Diabetic Mice ◽  
Intrauterine Environment ◽  
And Control ◽  
Picrosirius Red ◽  
Myocardial Collagen

Purpose. To investigate cardiomyopathy in offspring in a mouse model of pregestational type 1 diabetic pregnancy.Methods. Pregestational diabetes was induced with STZ administration in female C57BL6/J mice that were subsequently mated with healthy C57BL6/J males. Offspring were sacrificed at embryonic day 18.5 and 6-week adolescent and 12-week adult stages. The size and number of cardiomyocyte nuclei and also the extent of collagen deposition within the hearts of diabetic and control offspring were assessed following cardiac tissue staining with either haematoxylin and eosin or Picrosirius red and subsequently quantified using automated digital image analysis.Results. Offspring from diabetic mice at embryonic day 18.5 had a significantly higher number of cardiomyocyte nuclei present compared to controls. These nuclei were also significantly smaller than controls. Collagen deposition was shown to be significantly increased in the hearts of diabetic offspring at the same age. No significant differences were found between the groups at 6 and 12 weeks.Conclusions. Our results from offspring of type 1 diabetic mice show increased myocardial collagen deposition in late gestation and have increased myocardial nuclear counts (hyperplasia) as opposed to increased myocardial nuclear size (hypertrophy) in late gestation. These changes normalize postpartum after removal from the maternal intrauterine environment.

scholarly journals Effect of reduced dietary zinc intake on carbohydrate and Zn metabolism in the genetically diabetic mouse (C57BL/KsJ db+/db+)

1988 ◽  
Vol 60 (3) ◽  
pp. 499-507 ◽  
Author(s):  
Susan Southon ◽  
Z. Kechrid ◽  
A. J. A. Wright ◽  
Susan J. Fairweather-Tait
Keyword(s):  
Blood Glucose ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Liver Glycogen ◽  
Diabetic Mouse ◽  
Whole Body ◽  
Diabetic Mice ◽  
Control Groups ◽  
Glucose Levels ◽  
Blood Glucose Levels

1. Male, 4–5-week-old, genetically diabetic mice (C57BL/KsJ db/db) and non-diabetic heterozygote litter-mates (C57BL/KsJ db/+)were fed on a diet containing 1 mg zinc/kg (low-Zn groups) or 54 mg Zn/kg (control groups) for 27 d. Food intakes and body-weight gain were recorded regularly. On day 28, after an overnight fast, animals were killed and blood glucose and insulin concentrations, liver glycogen, and femur and pancreatic Zn concentrations were determined.2. The consumption of the low-Zn diet had only a minimal effect on the Zn status of the mice as indicated by growth rate, food intake and femur and pancreatic Zn concentrations. In fact, diabetic mice fed on the low-Zn diet had a higher total food intake than those fed on the control diet. The low-Zn diabetic mice had higher fasting blood glucose and liver glycogen levels than their control counterparts. Fasting blood insulin concentration was unaffected by dietary regimen.3. A second experiment was performed in which the rate of loss of 65Zn, injected subcutaneously, was measured by whole-body counting in the two mouse genotypes over a 28 d period, from 4 to 5 weeks of age. The influence of feeding low-Zn or control diets was also examined. At the end of the study femur and pancreatic Zn and non-fasting blood glucose levels were determined.4. All mice fed on the low-Zn diet showed a marked reduction in whole-body 65Zn loss compared with those animals fed on the control diet. In the low-Zn groups, the loss of 65Zn from the diabetic mice was significantly greater than that from heterozygote mice. This difference was not observed in the control groups. Blood glucose levels were elevated in the low-Zn groups. Possible reasons for these observations are discussed.5. The present study demonstrates an adverse effect of reduced dietary Zn intake on glucose utilization in the genetically diabetic mouse, which occurred before any significant tissue Zn depletion became apparent.

scholarly journals Loss of PDK1 Induces Meiotic Defects in Oocytes From Diabetic Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Juan Ge ◽  
Na Zhang ◽  
Shoubin Tang ◽  
Feifei Hu ◽  
Xiaojing Hou ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Maternal Diabetes ◽  
Diabetic Mouse ◽  
Oocyte Quality ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Dysfunction ◽  
Diabetic Mice ◽  
Α Subunit ◽  
Oocyte Competence ◽  
Beneficial Effects

Maternal diabetes has been shown to impair oocyte quality; however, the underlying mechanisms remain unclear. Here, using a streptozotocin (STZ)-induced diabetic mouse model, we first detected and reduced expression of pyruvate dehydrogenase kinase 1 (PDK1) in diabetic oocytes, accompanying with the lowered phosphorylation of serine residue 232 on α subunit of the pyruvate dehydrogenase (PDH) complex (Ser232-PDHE1α). Importantly, forced expression of PDK1 not only elevated the phosphorylation level of Ser232-PDHE1α, but also partly prevented the spindle disorganization and chromosome misalignment in oocytes from diabetic mice, with no beneficial effects on metabolic dysfunction. Moreover, a phospho-mimetic S232D-PDHE1α mutant is also capable of ameliorating the maternal diabetes-associated meiotic defects. In sum, our data indicate that PDK1-controlled Ser232-PDHE1α phosphorylation pathway mediates the effects of diabetic environment on oocyte competence.

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