Abstract
Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the histone deacetylase (HDAC) inhibitor class of agents. HDACs are a group of enzymes that remove functional acetyl groups from histone and non-histone proteins and they can affect cellular function through both epigenetic and non-epigenetic means. Over the past decade, several HDAC inhibitors have been adopted into clinical practice, primarily for the treatment of hematological malignancy, whereas other existing therapies (for instance valproate) have been found to have HDAC inhibitory effects. Here we review the current HDAC inhibitors in the clinic and under development; the literature evidence supporting the renoprotective effects of HDAC inhibitors in experimental diabetic kidney disease; and the adverse effect profiles that may prevent existing therapies from entering the clinic for this indication. Whereas recent research efforts have shed light on the fundamental actions of HDACs in the diabetic kidney, whether these efforts will translate into novel therapies for patients will require more specific and better-tolerated therapies.
Highlights
Kidney disease due to diabetes is the most common cause of chronic kidney failure across the globe [1]
We spotlight the current need for new treatments for diabetic kidney disease, we briefly summarize the biological effects of histone deacetylase (HDAC) and the various classes of pharmacological HDAC inhibitor that have been developed to date and we review the preclinical studies that have reported the effects of HDAC inhibitor treatment in experimental diabetic kidney disease
We treated STZ-diabetic mice with vorinostat (50 mg/kg/day) for 18 weeks, observing an attenuation in the development of albuminuria and a reduction in both glomerular collagen IV deposition and mesangial matrix accumulation [5]. We noticed that these improvements in kidney injury were associated with a reduction in oxidative stress and in exploring the mechanisms underlying this, we focused on the paradigm of endothelial nitric oxide synthase uncoupling [5]
Summary
Kidney disease due to diabetes is the most common cause of chronic kidney failure across the globe [1]. During the course of the past decade, a number of preclinical studies have emerged (including those from our own group [5,6]) that have demonstrated the efficacy of various HDAC inhibitors in experimental models of diabetic kidney disease. The term “diabetic nephropathy” denotes a chronic condition, originally described in the 1980s [7], that is characterized by the progressive appearance of incipient and overt albuminuria that precedes a decline in glomerular filtration rate (GFR), culminating in ESKD. This clinical condition is often associated with specific histopathological features, most notably the classical Kimmelsteil-Wilson lesion of nodular glomerulosclerosis. We focus on pre-clinical experimentation in which the effects of HDAC inhibitors have been studied in rodent models of diabetes, without other comorbidity, and we have chosen to employ the term “diabetic kidney disease”
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