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

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.

Identification and Verification of Potential Therapeutic Target Genes in Berberine-Treated Zucker Diabetic Fatty Rats through Bioinformatics Analysis

“…Excessive activation of the RHOA/ROCK signaling pathway plays an important role in the development of the chronic complications of diabetes [23]. RHOA also involved in renal integrity in diabetic mice, and its inhibitors attenuate diabetic nephropathy in different models of diabetes [24]. RHOA/ROCK signaling activated by TGF-β to regulate Nox4 activity, which might be associated with abnormalities in renal structure [25].…”

RhoGTPase in Vascular Disease

“…The beneficial effect of statins in vascular leak protection is due to inhibition of the geranyl-geranylation enzyme required for RhoA post-translational modification and activity [49,50]. Atorvastatin reduces vascular leak in diabetic mice by down-regulation of RhoA and up-regulation of Akt/GSK3 [51]. HDAC inhibitor studies suggest protection against sepsis-induced vascular leakage by suppressing Hsp90-dependent RhoA activity and signaling [52].…”

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

“…Established benefits of the lipid modulating agents, hydroxymethylglutaryl-CoA reductase (HMGCR) inhibitors, better known as statins, have been demonstrated in the setting of experimental diabetic nephropathy (Bruder-Nascimento et al, 2016;Kim et al, 2016). In human diabetic kidney disease, positive findings have been observed with statins, although this is not a universal finding (Colhoun et al, 2009;Abe et al, 2011;de Zeeuw et al, 2015).…”