Abstract
Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.
Highlights
Acute kidney injury (AKI) is a contributor to the Global Burden of Disease, and can severely impair the function and damage the structure of the kidney [1]
To determine if the protective effects of 4-PBA treatment were due to its histone deacetylase (HDAC) inhibitory effects, HK-2 cells were treated with TM, 4-PBA, or vorinostat
Thioflavin T staining demonstrated increased protein aggregation with TM treatment, which was prevented with the protein-folding chaperone 4-PBA; vorinostat had no effect on protein aggregation (Fig 1E)
Summary
Acute kidney injury (AKI) is a contributor to the Global Burden of Disease (defined by the World Health Organization), and can severely impair the function and damage the structure of the kidney [1]. AKI can occur due to pre-renal, renal or post-renal causes; the most common include ischemia [2, 3], nephrotoxic drugs [4], and radiocontrast medium [5]. These damaging insults cause acute tubular necrosis, which leads to tubular atrophy, loss of the brush border of the renal tubule, and cellular vacuolization of the tubular epithelium. An event of AKI increases a patient’s risk of chronic kidney disease, end stage renal disease, and premature death [6]. This illustrates the need for research to elucidate viable prevention and treatment options of AKI for patients
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