title: Greater efficacy of atorvastatin versus a non-statin lipid-lowering agent against renal injury: potential role as a histone deacetylase inhibitor.
abstract: Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors have been shown to improve diabetic nephropathy. However, whether they provide protection via Histone deacetylases (HDAC) inhibition is not clear. We conducted a comparative evaluation of Atorvastatin (AT) versus the non-statin cholesterol-lowering drug, Ezetimibe (EZT) on severity of diabetic nephropathy. Streptozotocin-treated male Wistar rats were fed a cholesterol-supplemented diet and gavaged daily with vehicle, AT or EZT. Control rats received normal diet and gavaged vehicle (n = 8-9/group). Diabetes increased blood glucose, urine albumin-to-creatinine ratio (ACR), kidney pathology and HDAC activity, and reduced renal E-cadherin levels. Both AT and EZT reduced circulating cholesterol, attenuated renal pathology, and did not lower blood glucose. However, AT was significantly more effective than EZT at reducing kidney pathology and HDAC activity. Chromatin immunoprecipitation revealed a significantly higher association of acetylated H3 and H4 with the E-cadherin promoter in kidneys from AT-, relative to EZT- or vehicle-treated rats. Moreover, we demonstrated a direct effect of AT, but not EZT, on HDAC-inhibition and, H3 and H4- acetylation in primary glomerular mesangial cells. Overall, both AT and EZT attenuated diabetic nephropathy; however, AT exhibited greater efficacy despite a similar reduction in circulating cholesterol. HDAC-inhibition may underlie greater efficacy of statins in attenuating kidney injury.
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Singh
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Dharmendra Kumar
authors.initials: DK
authors.lastname: Chaudhary
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Aradhana
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Chandra Prakash
authors.initials: CP
authors.lastname: Chaturvedi
authors.affiliation: Department of Medicine, Georgetown University, Washington DC, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ecelbarger
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
authors.affiliation: Department of Molecular Medicine &Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069438:Ezetimibe / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D007668:Kidney / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D056572:Histone Deacetylase Inhibitors; D000069059:Atorvastatin; D006655:Histone Deacetylases; D000069438:Ezetimibe