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

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Bruder-Nascimento, Thiago ; Callera, Glaucia ; Montezano, Augusto Cesar ; Antunes, Tayze T. ; He, Ying ; Cat, Aurelie Nguyen Dinh ; Ferreira, Nathanne S. ; Barreto, Pedro A. ; Olivon, Vania C. ; Tostes, Rita C. ; Touyz, Rhian M.

• Document type: Journal article
• Source: PLoS One; v. 11, n. 9 SEP 20 2016.
• Web of Science Citations: 4

Abstract

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 injurywas 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 injurywas 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/GSK3 beta 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/GSK3 beta signaling pathways. The present study provides some new insights into molecular mechanisms whereby statins may protect against renal injury in diabetes. (AU)

• FAPESP's process: 11/01785-6 - Contribution of oxidative stress and NOXes to diabetes-associated vascular injury
• Grantee: Thiago Bruder Do Nascimento
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/22035-5 - Contribution of oxidative stress and NADPH oxidase (NOXes) diabetes-associated vascular injury: study in knockout mice
• Grantee: Thiago Bruder Do Nascimento
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate