Differential effect of statins on diabetic nephropathy in db/db mice

Tamura, Yukinori; Murayama, Toshinori; Minami, Manabu; Yokode, Masayuki; Arai, Hidenori

doi:10.3892/ijmm.2011.769

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…In the present study, db/db mice, with genetic hyperglycemia akin to adult-onset T2DM as a consequence of an inactive gene mutation affecting leptin receptors, were specifically selected as the T2DM model ( 31 – 33 ); this model has been widely recognized to be well-established animal model for investigating the association between hyperglycemia, EPC function and wound closure ( 34 ). Wound healing following tissue damage is a sophisticated pathophysiological process which requires comprehensive interactions between cells and a variety of signaling molecules ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin accelerates wound healing in type 2 diabetic db/db mice

Han

Tao

Deng

et al. 2017

Molecular Medicine Reports

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Wound healing impairment is increasingly recognized to be a consequence of hyperglycemia-induced dysfunction of endothelial precursor cells (EPCs) in type 2 diabetes mellitus (T2DM). Metformin exhibits potential for the improvement of endothelial function and the wound healing process. However, the underlying mechanisms for the observed beneficial effects of metformin application remain to be completely understood. The present study assessed whether metformin, a widely used therapeutic drug for T2DM, may accelerate wound closure in T2DM db/db mice. Genetically hyperglycemic db/db mice were used as the T2DM model. Metformin (250 mg/kg/day; intragastric) was administered for two weeks prior to EPC collection and wound model creation in db/db mice. Wound healing was evaluated by alterations in the wound area and the number of platelet endothelial cell adhesion molecule-positive cells. The function of the isolated bone marrow-derived EPCs (BM-EPCs) was assessed by a tube formation assay. The number of circulating EPCs, and the levels of intracellular nitric oxide (NO) and superoxide (O2−) were detected by flow cytometry. Thrombospondin-1 (TSP-1) expression was determined by western blot analysis. It was observed that treatment with metformin accelerated wound healing, improved angiogenesis and increased the circulating EPC number in db/db mice. In vitro, treatment with metformin reversed the impaired BM-EPC function reflected by tube formation, and significantly increased NO production while decreasing O2− levels in BM-EPCs from db/db mice. In addition, TSP-1 expression was markedly attenuated by treatment with metformin in cultured BM-EPCs. Metformin contributed to wound healing and improved angiogenesis in T2DM mice, which was, in part, associated with stimulation of NO, and inhibition of O2− and TSP-1 in EPCs from db/db mice.

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Section: Discussionmentioning

confidence: 99%

Metformin accelerates wound healing in type 2 diabetic db/db mice

Han

Tao

Deng

et al. 2017

Molecular Medicine Reports

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“…However, several animal experiments demonstrated that statins exerted renal benefits that is independent on the lipid-lowering effect. Rosuvastatin treatment for 8 weeks reduced the excretion of urinary albumin and suppressed glomerular hypertrophy in db/db mice even though blood lipid levels were not altered by drug treatment [ 59 ]. In Apo-E knockout mice, rosuvastatin administration for 20 weeks showed renoprotective effects that are irrelevant to the lipid-lowering effect [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice

Kim

Choi

et al. 2016

PLoS ONE

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Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD.

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“…Our data are in agreement with these and other studies showing that statins improve renal structure both in type 1 and type 2 experimental diabetes [ 8 , 34 – 36 ] and also in patients with type 1 diabetes [ 37 ]. The effects of atorvastatin observed in our study do not seem to be agent-specific as other statins, such as simvastatin, pitavastatin and rosuvastatin have also been shown to have some renoprotective actions in experimental models of diabetes [ 8 , 38 ].…”

Section: Discussionmentioning

confidence: 58%

Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3

et al. 2016

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Potential benefits of statins in the treatment of chronic kidney disease beyond lipid-lowering effects have been described. However, molecular mechanisms involved in renoprotective actions of statins have not been fully elucidated. We questioned whether statins influence development of diabetic nephropathy through reactive oxygen species, RhoA and Akt/GSK3 pathway, known to be important in renal pathology. Diabetic mice (db/db) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p.o., for 2 weeks). Diabetes-associated renal injury was characterized by albuminuria (albumin:creatinine ratio, db/+: 3.2 ± 0.6 vs. db/db: 12.5 ± 3.1*; *P<0.05), increased glomerular/mesangial surface area, and kidney hypertrophy. Renal injury was attenuated in atorvastatin-treated db/db mice. Increased ROS generation in the renal cortex of db/db mice was also inhibited by atorvastatin. ERK1/2 phosphorylation was increased in the renal cortex of db/db mice. Increased renal expression of Nox4 and proliferating cell nuclear antigen, observed in db/db mice, were abrogated by statin treatment. Atorvastatin also upregulated Akt/GSK3β phosphorylation in the renal cortex of db/db mice. Our findings suggest that atorvastatin attenuates diabetes-associated renal injury by reducing ROS generation, RhoA activity and normalizing Akt/GSK3β signaling pathways. The present study provides some new insights into molecular mechanisms whereby statins may protect against renal injury in diabetes.

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Differential effect of statins on diabetic nephropathy in db/db mice

Cited by 6 publications

References 35 publications

Metformin accelerates wound healing in type 2 diabetic db/db mice

Metformin accelerates wound healing in type 2 diabetic db/db mice

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice

Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3

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