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.

Two‐year‐supervised resistance training prevented diabetes incidence in people with prediabetes: A randomised control trial

“…In this study, the use of statins and ezetimibe was reported by our participants. Ezetimibe's effect of decreasing blood glucose has been revealed by studies, while statins have been proved to increase the risk of developing type 2 diabetes . We analysed the effects of these medications on the results of this study.…”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…These drugs also have had favourable effects on renal function in clinical trials, particularly in patients with diabetes; long‐term therapy reduces albuminuria and retards the decline in glomerular filtration rate . Similar benefits to the kidney have been noted in experimental diabetes; in these studies, statins prevent oxidative stress and cellular injury as well as the inflammatory, proliferative and fibrotic changes that are characteristic of diabetic chronic renal disease . These favourable effects cannot be fully explained by the actions of these drugs on lipids; other lipid‐lowering drugs exert little or modest effects on albuminuria and may worsen renal function in patients with diabetes .…”

“…9,211,212 Similar benefits to the kidney have been noted in experimental diabetes; in these studies, statins prevent oxidative stress and cellular injury as well as the inflammatory, proliferative and fibrotic changes that are characteristic of diabetic chronic renal disease. [213][214][215][216][217][218][219][220] These favourable effects cannot be fully explained by the actions of these drugs on lipids; other lipid-lowering drugs exert little or modest effects on albuminuria and may worsen renal function in patients with diabetes. [221][222][223][224] It is therefore noteworthy that statins inhibit NHE activity in experimental and clinical studies.…”

The anti-lipidemic drug simvastatin modulates Epigenetic Biomarkers in the AmphipodGammarus locusta

“…This switch is accomplished by the modulation of acetylation of lysine 16 in histone H4 (H4K16ac), a DMAP1-induced, acting in inter-nucleosome interaction and as a scaffold for other transcription factors and chromatin-modifying proteins [92,93]. A growing body of evidences suggests that statins can promote the acetylation of H3 and H4 histones [45,78,94]. Thus, the increase of dmap1 transcription may be directly related with the increasing transcription of several genes or through the negative feedback required for the protection of the genome.…”

“…Although the underlying mechanism(s) of the observed SIM effects are poorly understood, previous studies with mammalian cell lines suggested that this pharmaceutical is able to modulate the regulation of the epigenome (e.g. DNA Methylation, histone acetylation and ncRNAs) [42][43][44][45][46]. Alterations in DNA methylation have previously been associated with downregulation or inhibition of DNA methyltransferase 1 (DNMT1), a critical protein responsible for maintenance of DNA methylation patterns [47,48].…”