HDAC inhibitors in experimental liver and kidney fibrosis

Abstract

Histone deacetylase (HDAC) inhibitors have been extensively studied in experimental models of cancer, where their inhibition of deacetylation has been proven to regulate cell survival, proliferation, differentiation and apoptosis. This in turn has led to the use of a variety of HDAC inhibitors in clinical trials. In recent years the applicability of HDAC inhibitors in other areas of disease has been explored, including the treatment of fibrotic disorders. Impaired wound healing involves the continuous deposition and cross-linking of extracellular matrix governed by myofibroblasts leading to diseases such as liver and kidney fibrosis; both diseases have high unmet medical needs which are a burden on health budgets worldwide. We provide an overview of the potential use of HDAC inhibitors against liver and kidney fibrosis using the current understanding of these inhibitors in experimental animal models and in vitro models of fibrosis.

Figure 1

Possible origins of myofibroblast-like cells in liver and kidney. It is recognized that the fibrogenic cells in both liver and kidney are heterogeneous in their origin and behavior. In general, matrix-producing cells in chronic wound repair are derived from resident fibroblasts, respectively portal fibroblasts in the liver and interstitial fibroblasts in the kidney. Besides fibroblasts, the major contributors to the excessive ECM deposition are specialized pericytes, such as hepatic stellate cells and mesangial cells. In vitro and in vivo evidence is available for the possibility of epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Finally, several studies have suggested that bone marrow-derived stem cells or fibrocytes could transdifferentiate within adult tissues to form mature matrix-producing cells; however, the amount of ECM produced by these cells appears to be negligible.

Figure 2

Multidisciplinary techniques for characterization of CCl₄-induced liver fibrosis and ADR-induced renal fibrosis. Although the liver and kidneys are very distinct organs, common techniques are available for detection of fibrotic damage in them. The top panel shows schemes of the functional units of the kidneys and liver, respectively the glomerulus and the hepatic lobule. Histological staining, Periodic Acid Schiff (PAS) or hematoxylin staining can be performed to study histological changes and are frequently combined with a Sirius Red staining to quantify the degree of matrix deposition or scar formation. Finally, QPCR analysis can provide further information on changes in gene expression upon organ fibrosis. Well-known markers are collagen 1 and alpha-smooth muscle actin, both representing the presence of matrix-producing myofibroblasts. CCl₄-induced liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (50 μg/100 g body weight) twice a week for four weeks in BalbC male mice. ADR-induced renal fibrosis was induced by a single intravenous injection of adriamycin (10 mg/kg body weight) and female mice were sacrificed 23 days after ADR injection. The study protocol was approved by the Institutional Animal Care and Use Committee of Vrije Universiteit Brussel, permit numbers 10-212-3 and 09-217-1 and National Institutes of Health principles of laboratory animal care (NIH publication 86–23, revised 1995) were followed. AA, afferent arteriole; CL, capillary loop; CV, central vein; EA, efferent arteriole; HA, hepatic artery; HEP, hepatocyte or hepatocytes; HPV, hepatic portal vein; HSC, hepatic stellate cell; M, mesangial cell; MD, macula densa; P, podocyte.

Figure 3

Overview of processes affected by HDAC inhibition in liver and kidney fibrosis. In experimental models of both liver and kidney fibrosis the beneficial effects of HDAC inhibitors have been reported as discussed in this review. (A) Specifically for liver, most studies have focused on the effects on stellate cell activation. Different aspects of this process have been described, such as, for example, the effects on matrix remodeling proteins. By inhibiting HSC activation, the development of fibrosis can be inhibited. (B) In kidneys, the favorable properties of HDAC inhibitors can be found in both the glomerular and tubulointerstitial compartment, where processes, such as proliferation, apoptosis, ECM deposition and inflammation, are hampered. Abrogating the pathological processes of glomerulosclerosis and tubulointerstitial (TI) fibrosis can potentially inhibit the development and progression of chronic kidney disease (CKD).