A model for diabetic nephropathy: Advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse

2008 ◽  
Vol 215 (2) ◽  
pp. 383-391 ◽  
Author(s):  
Akari Inada ◽  
Hiroshi Kanamori ◽  
Hidenori Arai ◽  
Tomoyuki Akashi ◽  
Makoto Araki ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transgenic Mouse ◽  
Diabetic Mouse ◽  
Inducible Camp Early Repressor

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.

scholarly journals Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy

2006 ◽  
Vol 70 (5) ◽  
pp. 882-891 ◽  
Author(s):  
Y. Wang ◽  
J. Zhou ◽  
A.W. Minto ◽  
B.K. Hack ◽  
J.J. Alexander ◽  
...  
Keyword(s):  
Vitamin D ◽  
Diabetic Nephropathy ◽  
Diabetic Mouse ◽  
Type Ii ◽  
Vitamin D Metabolism

scholarly journals Prevention of Diabetic Nephropathy by Sulforaphane: Possible Role of Nrf2 Upregulation and Activation

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Wenpeng Cui ◽  
Yang Bai ◽  
Xiao Miao ◽  
Ping Luo ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Diabetic Mouse ◽  
Protective Effects ◽  
Sustained Effect ◽  
Renal Tubular ◽  
Prevention Of Diabetes ◽  
Nrf2 Expression

The present study was to investigate whether sulforaphane (SFN) can prevent diabetic nephropathy in type 1 diabetic mouse model induced by multiple low-dose streptozotocin. Diabetic and age-matched control mice were given SFN at 0.5 mg/kg body weight daily for 3 months. At the end of 3-month SFN treatment, the diabetic nephropathy, shown by renal inflammation, oxidative damage, fibrosis, and dysfunction, was significantly prevented along with an elevation of renal Nrf2 expression and transcription in diabetes/SFN group compared with diabetic group. However, this renal prevention by SFN was not seen when the 3-month SFN-treated diabetic mice were aged for additional 3 months without further SFN treatment. Nrf2-mediated renal protective effects in diabetes were evaluated in human renal tubular HK11 cells transfected with control and Nrf2 siRNA and treated with 27.5 mM mannitol or high glucose plus palmitate (300 μM). Blockade of Nrf2 expression completely abolished SFN prevention of the profibrotic effect induced by high glucose plus palmitate. These results support that renal Nrf2 expression and its transcription play important roles in SFN prevention of diabetes-induced renal damage. However, the SFN preventive effect on diabetes-induced renal pathogeneses is not sustained, suggesting the requirement of continual use of SFN for its sustained effect.

scholarly journals Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy

2021 ◽  
Vol 22 (11) ◽  
pp. 5491
Author(s):  
Yuya Takahashi ◽  
Tatsunori Shimizu ◽  
Shunsuke Kato ◽  
Mitsuhiko Nara ◽  
Yumi Suganuma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Diabetic Nephropathy ◽  
Muscle Regeneration ◽  
Diabetic Mouse ◽  
Skeletal Muscle Regeneration ◽  
Oxidative Stress Marker ◽  
Regeneration Capacity ◽  
Cross Sectional

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.

scholarly journals Maslinic Acid Activates Renal Ampk/sirt1 Signaling Pathway to Protect Against Diabetic Nephropathy in Mice

2021 ◽  
Author(s):  
Huijuan Gao ◽  
Hong Wu
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Acid Treatment ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Pentacyclic Triterpene ◽  
Triterpene Acid ◽  
Maslinic Acid

Abstract BackgroundDiabetic nephropathy has been a devastating complication. Clinically, there is an urgent need for nephroprotective agents to delay the onset of diabetic nephropathy and ameliorate its symptoms. Maslinic acid is a pentacyclic triterpene acid with protective effect on multiple organs from oxidative stress and inflammation. However, the therapeutic effect of maslinic acid on diabetic nephropathy remains unclear.MethodsC57BL/6J male mice administrated with 50 mg/kg of Streptozocin (STZ) daily were used to establish diabetic mouse model (blood glucose levels > 300 mg/dL). Urinary levels of albumin, total proteins, and creatinine were analyzed by an automatic analyzer. H&E staining was used to evaluate renal damage. qRT-PCR and ELISA assay were performed to investigate the inflammation and oxidative stress of renal tissues. Western-blotting assay was used to demonstrate the activation of AMPK signaling.ResultsMaslinic acid treatment alleviated the loss of body weight and blood glucose in diabetic mice. The renal structure and function were protected by maslinic acid in diabetic mice. 20 mg/kg maslinic acid treatment for 8 weeks alleviated the oxidative stress and inflammation in the kidney of diabetic rats dramatically. Maslinic acid treatment activated renal AMPK/SIRT1 signaling.ConclusionMaslinic acid ameliorated diabetic nephropathy via activating AMPK/SIRT1 signaling pathway.

scholarly journals Distinct roles of arginases 1 and 2 in diabetic nephropathy

2017 ◽  
Vol 313 (4) ◽  
pp. F899-F905 ◽  
Author(s):  
Sidney M. Morris ◽  
Hanning You ◽  
Ting Gao ◽  
Jean Vacher ◽  
Timothy K. Cooper ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Albumin Excretion Rate ◽  
Selective Inhibition ◽  
Diabetic Mouse ◽  
Macrophage Infiltration ◽  
Mrna Levels ◽  
Plasma Urea ◽  
Economic Productivity ◽  
Arginase 1

Diabetes is the leading cause of end-stage renal disease, resulting in a significant health care burden and loss of economic productivity by affected individuals. Because current therapies for progression of diabetic nephropathy (DN) are only moderately successful, identification of underlying mechanisms of disease is essential to develop more effective therapies. We showed previously that inhibition of arginase using S-(2-boronoethyl)-l-cysteine (BEC) or genetic deficiency of the arginase-2 isozyme was protective against key features of nephropathy in diabetic mouse models. However, those studies did not determine whether all markers of DN were dependent only on arginase-2 expression. The objective of this study was to identify features of DN that are associated specifically with expression of arginase-1 or −2. Elevated urinary albumin excretion rate and plasma urea levels, increases in renal fibronectin mRNA levels, and decreased renal medullary blood flow were associated almost completely and specifically with arginase-2 expression, indicating that arginase-2 selectively mediates major aspects of diabetic renal injury. However, increases in renal macrophage infiltration and renal TNF-α mRNA levels occurred independent of arginase-2 expression but were almost entirely abolished by treatment with BEC, indicating a distinct role for arginase-1. We therefore generated mice with a macrophage-specific deletion of arginase-1 ( CD11bCre/ Arg1fl/fl). CD11bCre/ Arg1fl/fl mice had significantly reduced macrophage infiltration but had no effect on albuminuria compared with Arg1fl/fl mice after 12 wk of streptozotocin-induced diabetes. These results indicate that selective inhibition of arginase-2 would be effective in preventing or ameliorating major features of diabetic renal injury.

scholarly journals TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1

2010 ◽  
Vol 299 (5) ◽  
pp. F965-F972 ◽  
Author(s):  
Elizabeth Morse ◽  
Jana Schroth ◽  
Young-Hyun You ◽  
Donald P. Pizzo ◽  
Shinichi Okada ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Treatment Strategies ◽  
Diabetic Mouse ◽  
Endoplasmic Reticulum Stress Response ◽  
Cellular Survival ◽  
Homologous Protein ◽  
Elevated Glucose ◽  
Novel Treatment Strategies

The prevalence of diabetic nephropathy continues to rise, highlighting the importance of investigating and discovering novel treatment strategies. TRB3 is a kinase-like molecule that modifies cellular survival and metabolism and interferes with signal transduction pathways. Herein, we report that TRB3 expression is increased in the kidneys of type 1 and type 2 diabetic mice. TRB3 is expressed in conditionally immortalized podocytes; however, it is not stimulated by elevated glucose. The diabetic milieu is associated with increased oxidative stress and circulating free fatty acids (FFA). We show that reactive oxygen species (ROS) such as H2O2 and superoxide anion (via the xanthine/xanthine oxidase reaction) as well as the FFA palmitate augment TRB3 expression in podocytes. C/EBP homologous protein (CHOP) is a transcription factor that is associated with the endoplasmic reticulum stress response. CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. In podocytes, transfection of CHOP increases TRB3 expression, and ROS augment recruitment of CHOP to the proximal TRB3 promoter. MCP-1/CCL2 is a chemokine that contributes to the inflammatory injury associated with diabetic nephropathy. In these studies, we demonstrate that TRB3 can inhibit basal and stimulated podocyte production of MCP-1. In summary, enhanced ROS and/or FFA associated with the diabetic milieu induce podocyte CHOP and TRB3 expression. Because TRB3 inhibits MCP-1, manipulation of TRB3 expression could provide a novel therapeutic approach in diabetic kidney disease.

scholarly journals An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Masaya Koshizaka ◽  
Minoru Takemoto ◽  
Seiya Sato ◽  
Hirotake Tokuyama ◽  
Masaki Fujimoto ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Diabetic Mouse ◽  
Notch Signaling Pathway ◽  
Receptor Blocker ◽  
Cell Plasma ◽  
Akita Mice

Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factorβand vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

scholarly journals Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Liwen Zhang ◽  
Ying Zhou ◽  
Fangfang Zhou ◽  
Xialian Yu ◽  
Jian Liu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Bioinformatic Analysis ◽  
Diabetic Mouse ◽  
Therapeutic Effects ◽  
Messenger Rnas ◽  
Altered Expression ◽  
Normal Expression ◽  
Regulatory Approach ◽  
Rosiglitazone Treatment ◽  
Regulatory Effects

Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. These findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.

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