Histone Deacetylase Inhibitors and Diabetic Kidney Disease

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.

Keywords: acetylation; diabetes; epigenetics; histone; kidney disease; nephropathy.

Figure 1

Classes of histone deacetylase (HDAC) enzymes in humans.

Figure 2

Cellular effects of histone deacetylases (HDACs) and HDAC inhibitors (HDACis). In the normal state (left) HDAC enzymes mediate the enzymatic removal of functional acetyl groups (Ac) from lysine residues on histone and non-histone proteins. In the nucleus, histone protein acetylation (regulated by histone acetyltransferase (HAT) enzymes) can epigenetically affect gene transcription by causing a more open chromatin configuration permitting access by the transcriptional machinery and by serving as a recognition point for bromodomains possessed by transcriptional regulatory complexes, whereas histone deacetylation has the opposite effect. Some HDAC enzymes also have effects on non-histone proteins. For instance, SIRT3, SIRT4, and SIRT5 are mitochondrial proteins, whereas HDAC6 is localized primarily in the cytosol where it deacetylates proteins including α-tubulin. Pharmacological HDAC inhibition (right) can increase the acetylation of both histone and non-histone proteins resulting in both epigenetic and non-epigenetic effects on cell function.