12 research outputs found

    Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive- and Akt-dependent pathways

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    Chemerin and its G protein-coupled receptor [chemerin receptor 23 (ChemR23)] have been associated with endothelial dysfunction, inflammation, and insulin resistance. However, the role of chemerin on insulin signaling in the vasculature is still unknown. We aimed to determine whether chemerin reduces vascular insulin signaling and whether there is interplay between chemerin/ChemR23, insulin resistance, and vascular complications associated with type 2 diabetes (T2D). Molecular and vascular mechanisms were probed in mesenteric arteries and cultured vascular smooth muscle cells (VSMCs) from C57BL/6J, nondiabetic lean db/m, and diabetic obese db/db mice as well as in human microvascular endothelial cells (HMECs). Chemerin decreased insulin-induced vasodilatation in C57BL/6J mice, an effect prevented by CCX832 (ChemR23 antagonist) treatment. In VSMCs, chemerin, via oxidative stress- and ChemR23-dependent mechanisms, decreased insulin-induced Akt phosphorylation, glucose transporter 4 translocation to the membrane, and glucose uptake. In HMECs, chemerin decreased insulin-activated nitric oxide signaling. AMP-activated protein kinase phosphorylation was reduced by chemerin in both HMECs and VSMCs. CCX832 treatment of db/db mice decreased body weight, insulin, and glucose levels as well as vascular oxidative stress. CCX832 also partially restored vascular insulin responses in db/db and high-fat diet-fed mice. Our novel in vivo findings highlight chemerin/ChemR23 as a promising therapeutic target to limit insulin resistance and vascular complications associated with obesity-related diabetes

    Upregulation of Nrf2 and decreased redox signaling contribute to renoprotective effects of chemerin receptor blockade in diabetic mice

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    Chemerin, acting through its receptor ChemR23, is an adipokine associated with inflammatory response, glucose and lipid metabolism and vascular function. Although this adipokine has been associated with the development and progression of kidney disease, it is not clear whether the chemerin/ChemR23 system plays a role in renal function in the context of diabetes. Therefore, we sought to determine whether ChemR23 receptor blockade prevents the development and/or progression of diabetic nephropathy and questioned the role of oxidative stress and Nrf2 in this process. Renal redox state and function were assessed in non-diabetic lean db/m and diabetic obese db/db mice treated with vehicle or CCX832 (ChemR23 antagonist). Renal reactive oxygen species (ROS) production, which was increased in diabetic mice, was attenuated by CCX832. This was associated with an increase in Nox 4 expression. Augmented protein oxidation in db/db mice was not observed when mice were treated with CCX832. CCX832 also abrogated impaired Nrf2 nuclear activity and associated downregulation in antioxidants expression in kidneys from db/db mice. Our in vivo findings highlight the role of the redox signaling and Nrf2 system as renoprotective players during chemerin receptor blockade in diabetic mice. The chemerin/ChemR23 system may be an important target to limit renal dysfunction associated with obesity-related diabetes

    Renoprotective effects of atorvastatin in diabetic mice: downregulation of RhoA and upregulation of Akt/GSK3

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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

    Atorvastatin does not change expression of inflammatory markers in the renal cortex of db/db mice.

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    <p>Phosphorylation of NF-κB p65 (A) and the expression of OPN (B) and VCAM-1 (C) were evaluated in renal cortex isolated from db/+ and db/db mice treated with atorvastatin (10 mg/kg/day for 2 weeks) or control diet. Top panels, representative immunoblots of NF-κB p65 [Ser<sup>536</sup>], OPN, VCAM-1 and β-actin. Results are mean ± SEM of 6–8 mice in each experimental group. *, <i>P</i>< 0.05 <i>vs</i>. db/+ control diet.</p

    Atorvastatin reduces RhoA translocation from cytosol to the membane in kidneys of diabetic mice.

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    <p>RhoA translocation (A) and RhoA immunolocalization (B) from renal cortex obtained from db/+ and db/db mice treated with atorvastatin (10 mg/kg/day for 2 weeks) or control diet. Translocation of RhoA was assessed by protein expression in the membrane and cytosolic fractions isolated from renal cortex homogenates. Results are mean ± SEM of 3–6 mice in each experimental group. *P< 0.05 vs. db/+ control diet, **P<0.05 db/db atorvastatin diet vs. db/db control diet.</p

    Increased renal ERK1/2 MAPK phosphorylation is abrogated by atorvastatin in db/db mice.

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    <p>Phosphorylation levels of SAPK/JNK MAPK (A), p38 MAPK (B), and ERK1/2 MAPK (C) were evaluated in renal cortex isolated from db/+ and db/db mice treated with atorvastatin (10 mg/kg/day for 2 weeks) or control diet. Top panels, representative immunoblots of SAPK/JNK MAPK [Thr<sup>183</sup>/Tyr<sup>185</sup>], p38 MAPK [Thr<sup>180</sup>/Tyr<sup>182</sup>], ERK1/2 MAPK [Thr<sup>202</sup>/Tyr<sup>204</sup>] and β-actin. Results are presented as mean ± SEM of 6–8 mice in each experimental group. *P< 0.05 vs. db/+ control diet, **P<0.05 db/db atorvastatin diet vs. db/db control diet.</p

    Reduced Akt and GSK3β phosphorylation in the renal cortex of db/db mice is restored by atorvastatin.

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    <p>Phosphorylation levels of Akt (A) and GSK3β (B) were evaluated in renal cortex isolated from db/+ and db/db mice treated with atorvastatin (10 mg/kg/day for 2 weeks) or control diet. Top panels, representative immunoblots of Akt [Ser<sup>473</sup>], GSK3β [Ser<sup>9</sup>] and β-actin. Results are mean ± SEM of 6–8 mice in each experimental group. *P< 0.05 vs. db/+ control diet, **P<0.05 db/db atorvastatin diet vs. db/db control diet.</p

    Atorvastatin treatment reduces mesangial expansion in db/db mice.

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    <p>Graphs depict albuminuria (A), glomerular surface area (B), mesangial area, in blue (C) and representative images of a single glomerulus stained with Masson Trichrome (D) from db/+ and db/db mice treated with atorvastatin (10 mg/kg/day for 2 weeks) or control diet. Results are presented as mean ± SEM of 20 glomerular and mesangial areas in sections from 5 mice in each group. *P< 0.05 vs. db/+ control diet, **P<0.05 vs. db/db atorvastatin diet vs. db/db control diet and db/+ atorvastatin diet. (Black scale bar: 10 μm, magnification x100).</p
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