Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy

Recent studies suggest that thiazolidinediones ameliorate diabetic nephropathy (DN) independently of their effect on hyperglycemia. In the current study, we confirm and extend these findings by showing that rosiglitazone treatment prevented the development of DN and reversed multiple markers of oxidative injury in DBA/2J mice made diabetic by low-dose streptozotocin. These diabetic mice developed a 14.2-fold increase in albuminuria and a 53% expansion of renal glomerular extracellular matrix after 12 wk of diabetes. These changes were largely abrogated by administration of rosiglitazone beginning 2 wk after the completion of streptozotocin injections. Rosiglitazone had no effect on glycemic control. Rosiglitazone had similar effects on insulin-treated diabetic mice after 24 wk of diabetes. Podocyte loss and glomerular fibronectin accumulation, other markers of early DN, were prevented by rosiglitazone in both 12- and 24-wk diabetic models. Surprisingly, glomerular GLUT1 levels did not increase and nephrin levels did not decrease in the diabetic animals; neither changed with rosiglitazone. Plasma and kidney markers of protein oxidation and lipid peroxidation were significantly elevated in the 24-wk diabetic animals despite insulin treatment and were reduced to near-normal levels by rosiglitazone. Finally, urinary metabolites were markedly altered by diabetes. Of 1,988 metabolite features identified by electrospray ionization time of flight mass spectrometry, levels of 56 were altered more than twofold in the urine of diabetic mice. Of these, 21 were returned to normal by rosiglitazone. Thus rosiglitazone has direct effects on the renal glomerulus to reduce reactive oxygen species accumulation to prevent type 1 diabetic mice from development of DN.

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High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1600511113 ◽

2016 ◽

Vol 113 (8) ◽

pp. 2218-2222 ◽

Cited By ~ 18

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.

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FP412THE COMPARATIVE EFFECT OF SELECTIVE ADENOSINE 3 RECEPTOR ANTAGONIST AND ANGIOTENSIN RECEPTOR BLOCKADE ON DIABETIC NEPHROPATHY IN TYPE 1 DIABETIC MICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy104.fp412 ◽

2018 ◽

Vol 33 (suppl_1) ◽

pp. i174-i175

Author(s):

Dae Cha ◽

Hye Min ◽

Jin Cha ◽

Young Kang ◽

Ho Lee ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Receptor Antagonist ◽

Receptor Blockade ◽

Diabetic Mice ◽

Angiotensin Receptor ◽

Comparative Effect ◽

Angiotensin Receptor Blockade

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Apelin retards the progression of diabetic nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00306.2012 ◽

2013 ◽

Vol 304 (6) ◽

pp. F788-F800 ◽

Cited By ~ 50

Author(s):

Robert T. Day ◽

Rita C. Cavaglieri ◽

Denis Feliers

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Renin Angiotensin System ◽

Prolonged Treatment ◽

Glomerular Hypertrophy ◽

Diabetic Mice ◽

Short Treatment ◽

Renal Inflammation ◽

Monocyte Chemoattractant Protein 1

Apelin and its receptor APJ have pleiotropic effects in mice and humans and play a protective role in cardiovascular diseases at least partially by inhibiting oxidative stress. Our objective was to study the effect of apelin on the progression of kidney disease in mice with established type 1 diabetes. Ove26 mice with type 1 diabetes received daily subcutaneous injections of apelin for 2 or 14 wk. APJ localizes in the glomeruli and blood vessels of kidneys. Renal APJ expression was reduced in diabetic mice but increased after treatment with apelin. Apelin treatment did not affect glycemia, body weight, or blood pressure in diabetic mice. Whole kidney and glomerular hypertrophy, as well as renal inflammation, including monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression, NF-κB activation, and monocyte infiltration, was inhibited after short and long treatment with apelin. Apelin administration significantly reduced albuminuria at 6 mo. Short treatment with apelin was sufficient to reverse the downregulation of the antioxidant enzyme catalase. Expression of angiotensin II and angiotensin type 1 receptor (AT1) in kidneys from diabetic mice treated was not affected by apelin. These findings show for the first time that apelin exerts a protective effect on the diabetic kidney. Short administration is sufficient to reduce kidney and glomerular hypertrophy as well as renal inflammation, but prolonged treatment is required to improve albuminuria. This effect was independent of the activation of the renin angiotensin system but correlated with upregulation of the antioxidant catalase. Apelin may represent a novel tool to treat diabetic nephropathy.

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Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.00396.2014 ◽

2015 ◽

Vol 308 (11) ◽

pp. F1276-F1287 ◽

Cited By ~ 98

Author(s):

Yves Gorin ◽

Rita C. Cavaglieri ◽

Khaled Khazim ◽

Doug-Yoon Lee ◽

Francesca Bruno ◽

...

Keyword(s):

Type 1 Diabetes ◽

Nadph Oxidase ◽

Type Iv Collagen ◽

Renal Cortex ◽

Critical Role ◽

Diabetic Mice ◽

Type Iv ◽

Podocyte Loss ◽

Matrix Expansion

Reactive oxygen species (ROS) generated by Nox NADPH oxidases may play a critical role in the pathogenesis of diabetic nephropathy (DN). The efficacy of the Nox1/Nox4 inhibitor GKT137831 on the manifestations of DN was studied in OVE26 mice, a model of type 1 diabetes. Starting at 4–5 mo of age, OVE26 mice were treated with GKT137831 at 10 or 40 mg/kg, once-a-day for 4 wk. At both doses, GKT137831 inhibited NADPH oxidase activity, superoxide generation, and hydrogen peroxide production in the renal cortex from diabetic mice without affecting Nox1 or Nox4 protein expression. The increased expression of fibronectin and type IV collagen was reduced in the renal cortex, including glomeruli, of diabetic mice treated with GKT137831. GKT137831 significantly reduced glomerular hypertrophy, mesangial matrix expansion, urinary albumin excretion, and podocyte loss in OVE26 mice. GKT137831 also attenuated macrophage infiltration in glomeruli and tubulointerstitium. Collectively, our data indicate that pharmacological inhibition of Nox1/4 affords broad renoprotection in mice with preexisting diabetes and established kidney disease. This study validates the relevance of targeting Nox4 and identifies GKT137831 as a promising compound for the treatment of DN in type 1 diabetes.

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512-P: Sexual Differences in Progression of Diabetic Nephropathy in over 26 Type 1 Diabetic Mice

Diabetes ◽

10.2337/db19-512-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 512-P

Author(s):

WANNING WANG ◽

LU CAI

Keyword(s):

Diabetic Nephropathy ◽

Sexual Differences ◽

Diabetic Mice

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Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen

BioMed Research International ◽

10.1155/2016/9172157 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 22

Author(s):

Kyoko Nitta ◽

Sen Shi ◽

Takako Nagai ◽

Megumi Kanasaki ◽

Munehiro Kitada ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Oral Administration ◽

Kidney Diseases ◽

Combination Group ◽

Peptide Drug ◽

Diabetic Mice ◽

Kidney Fibrosis ◽

Type 2 Diabetic

Kidney fibrosis is the final common pathway of progressive kidney diseases including diabetic nephropathy. Here, we report that the endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. We utilized two mouse models of diabetic nephropathy, streptozotocin- (STZ-) induced type 1 diabetic CD-1 mice and type 2 diabetic nephropathy modeldb/dbmice. Intervention with the ACE inhibitor imidapril, oral AcSDKP, or imidapril + oral AcSDKP combination therapy increased urine AcSDKP levels. AcSDKP levels were significantly higher in the combination group compared to those of the other groups. AcSDKP oral administration, either AcSDKP alone or in addition to imidapril, ameliorated glomerulosclerosis and tubulointerstitial fibrosis. Plasma cystatin C levels were higher in both models, at euthanasia, and were restored by all the treatment groups. The levels of antifibrotic miRs, such as miR-29 or let-7, were suppressed in the kidneys of both models; all treatments, especially the combination of imidapril + oral AcSDKP, restored the antifibrotic miR levels to a normal value or even higher. AcSDKP may be an oral antifibrotic peptide drug that would be relevant to combating fibroproliferative kidney diseases such as diabetic nephropathy.

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