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 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.
Highlights
Kidney disease is associated with end-stage renal disease and continues to be a major cause of morbidity and mortality in patients with diabetes [1,2,3]
Considering that some of the beneficial effects of statins are mediated by antioxidant effects and RhoA inhibition [16, 18], the aim of the present study was to determine whether atorvastatin decreases RhoA activity, ROS signaling and associated renal damage in the leptin receptor deficient db/db mouse, a rodent model of obesity and type 2 diabetes
Obesity and diabetes are major co-morbidities associated with cardiovascular complications, nephropathy and end stage-renal disease
Summary
Kidney disease is associated with end-stage renal disease and continues to be a major cause of morbidity and mortality in patients with diabetes [1,2,3]. Several factors contribute to the progression of diabetic nephropathy, including hyperglycemia, hypertension, dyslipidemia, production of inflammatory cytokines and oxidative stress, triggering hypertrophic, proliferative, PLOS ONE | DOI:10.1371/journal.pone.0162731. Atorvastatin Attenuates Renal Damage in db/db Mice Several factors contribute to the progression of diabetic nephropathy, including hyperglycemia, hypertension, dyslipidemia, production of inflammatory cytokines and oxidative stress, triggering hypertrophic, proliferative, PLOS ONE | DOI:10.1371/journal.pone.0162731 September 20, 2016
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