Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats

Renin angiotensin system plays a major role in the pathology of progressive Diabetic Nephropathy. In the present study, the renoprotective effects of low dose combined novel direct renin inhibitor-aliskiren and angiotensin II type 1 receptor blocker (ARB)-valsartan were estimated and compared with monotherapy in wistar rats. Rats were divided into 5 groups: control, diabetic control, diabetic rats treated with aliskiren (10 mg/kg/day), valsartan (20 mg/kg/day) and combination of aliskiren and valsartan (5 mg/kg/day, 10mg/kg/day respectively). Clinical characteristics like proteinuria, serum creatinine and renal histopathological studies like glomerulosclrotic index, tubulointerstitial fibrosis were estimated and compared between all diabetic rats. Results showed that combination therapy of aliskiren and valsartan was more effective than the monotherapy in progressive diabetic nephropathy.

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Liraglutide suppresses production of extracellular matrix proteins and ameliorates renal injury of diabetic nephropathy by enhancing Wnt/β-catenin signaling

AJP Renal Physiology ◽

10.1152/ajprenal.00128.2020 ◽

2020 ◽

Vol 319 (3) ◽

pp. F458-F468 ◽

Cited By ~ 3

Author(s):

Linjing Huang ◽

Tingting Lin ◽

Meizhen Shi ◽

Xiuqing Chen ◽

Peiwen Wu

Keyword(s):

Diabetic Nephropathy ◽

Collagen Type ◽

Mesangial Cells ◽

Smooth Muscle Actin ◽

Diabetic Rats ◽

Collagen Type Iv ◽

Signaling Proteins ◽

Muscle Actin ◽

Type Iv

The Wnt/β-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/β-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/β-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3β, and β-catenin. These HG effects on Wnt/β-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 μg·kg−1·12 h−1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/β-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/β-catenin signaling.

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Combination of Naringenin and Lisinopril Ameliorates Nephropathy in Type-1 Diabetic Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200516163919 ◽

2020 ◽

Vol 20 ◽

Author(s):

Yogesh A. Kulkarni ◽

Sachin V. Suryavanshi

Keyword(s):

Oxidative Stress ◽

Diabetic Nephropathy ◽

Renal Damage ◽

Diabetic Rats ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Glycation End Products ◽

Histopathological Studies ◽

Diabetes Induction

Background: Diabetes is a metabolic disorder affecting large percentage of population worldwide. Chronic hyperglycemic condition leads to generation of advanced glycation end products, reactive oxygen species and inflammatory cytokines, which worsen functioning of kidney. Clinical management of diabetic nephropathy is difficult as it requires multifocused approach. Hence, Combination of lisinopril a drug used in clinical practice for nephropathy and naringenin, a flavonoid reported to have significant effect in nephropathy may show additive of synergistic effect with less side effects. Objective: The objective of present study was to evaluate the effect of combination of lisinopril with naringenin in diabetic nephropathy. Methods: Diabetes was induced in male Sprague Dawley rats by streptozotocin (55 mg/kg, i.p.). After four weeks of diabetes induction animals were treated with naringenin alone and combination of Lisinopril and naringenin for next four weeks. At the end of study, various urine and biochemical parameters were evaluated. Oxidative stress parameters like malondialdehyde, reduced glutathione; catalase and superoxide dismutase for kidney tissues were estimated and histopathology studies of kidney were carried out. Results: Combination of lisinopril (10 mg/kg) and naringenin (25 and 50 mg/kg) treatment showed significant improvement in the biochemical and urine parameters. Combination treatment also attenuated renal oxidative stress and renal damage as observed in histopathological studies. Conclusion: Treatment with combination of lisinopril and naringenin showed promising effect in diabetic nephropathy in rats.

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Amelioration of STZ-induced nephropathy in diabetic rats by saffron hydro alcoholic extract

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2021-0005 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Jamal Amri ◽

Mona Alaee ◽

Seyed Amirhossein Latifi ◽

Abbas Alimoradian ◽

Mehdi Salehi

Keyword(s):

Oxidative Stress ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Microvascular Complications ◽

Kidney Tissue ◽

Diabetic Rats ◽

Alcoholic Extract ◽

Serum Urea ◽

Sod Activity

Abstract Objectives Type 1 diabetes is one of the most important causes of microvascular complications such as nephropathy. On other hand, the use of herbal medicines is more affordable and has fewer side effects. Therefore, this study was conducted to assessment the therapeutic effect of saffron in diabetic nephropathy by regulating the expression of CTGF and RAGE genes as well as oxidative stress in rats with type 1 diabetes. Methods In this study, we used 24 Wistar rats in four groups. To induce diabetes, we used a 55 mg/kg.bw dose of streptozotocin intraperitoneally. Type 1 diabetic rats were administered saffron (20 and 40 mg/kg/day) by gavage once daily for 42 days. Finally, serum urea, creatinine, albumin and SOD, MDA levels in kidney tissue were measured using spectrophotometric methods and CTGF and RAGE gene expression in kidney tissue was measured using real-time PCR method. Results Diabetes significantly increases serum FBG, urea, creatinine and decreases albumin (p<0.001). AS well as increased the CTGF and RAGE genes expression, MDA level and decreased the SOD activity in the kidney tissue (p<0.001). Serum urea, creatinine, albumin was significantly ameliorated by saffron (p<0.001). It was shown the saffron significantly decrease the kidney expression CTGF and RAGE genes and MDA level and increased the SOD activity (p<0.001). Also, it was found that the beneficial effects of the saffron were dose-dependent (p<0.05). Conclusions The results of this study suggest that saffron as an adjunct therapy may prevent development and treatment of diabetic nephropathy by regulating the expression of the CTGF and RAGE genes and oxidative stress.

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Eucommia bark (Du-Zhong) improves diabetic nephropathy without altering blood glucose in type 1-like diabetic rats

Drug Design Development and Therapy ◽

10.2147/dddt.s98558 ◽

2016 ◽

pp. 971 ◽

Cited By ~ 4

Author(s):

Juei-Tang Cheng ◽

Ho-Shan Niu ◽

I-Min Liu ◽

Chiang-Shan Niu ◽

Po-Ming Ku ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Blood Glucose ◽

Diabetic Rats

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Poly(Adenosine 5′-Diphosphate-Ribose) Polymerase Inhibition Counteracts Multiple Manifestations of Experimental Type 1 Diabetic Nephropathy

Endocrinology ◽

10.1210/en.2009-0628 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5273-5283 ◽

Cited By ~ 18

Author(s):

Viktor R. Drel ◽

Weizheng Xu ◽

Jie Zhang ◽

Ivan A. Pavlov ◽

Hanna Shevalye ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Western Blot ◽

Blot Analysis ◽

Renal Cortex ◽

Parp Inhibitors ◽

Diabetic Rats ◽

Parp Inhibition ◽

Tnf Α

Abstract This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg−1 · d−1 ip and 30 mg/kg−1 · d−1, respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-β1, vascular endothelial growth factor, endothelin-1, TNF-α, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-α excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-α1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies.

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