Determining how 4‐phenylbutyrate inhibits tunicamycininduced acute kidney injury

It has been demonstrated that many nephrotoxic drugs, such as tunicamycin, induce endoplasmic reticulum (ER) stress as part of the mechanism by which they cause acute kidney injury (AKI). There are three main mechanisms by which the low molecular weight chemical chaperone 4‐phenylbutyrate (4‐PBA) can modify AKI: (1) as a histone deacetylase inhibitor, (2) as an ER stress inhibitor, and (3) as a mediator of waste nitrogen excretion. We hypothesized that 4‐PBA would inhibit tunicamycin‐induced acute kidney injury using one of these three mechanisms. C57BL/6J mice were either untreated or pre‐treated with 4‐PBA for one week, at a dose of 1 g/kg, delivered in the drinking water. Proximal tubular cell injury was then induced by intraperitoneal injection of tunicamycin (0.5 mg/kg) for 3 days. In the whole animal, tunicamycin was found to induce proximal tubule injury in the juxtamedullary region, demonstrated by the presence of tubular epithelial cell vacuolization, in PAS‐stained sections. 4‐PBA pretreatment reduced the injury score associated with tunicamycin‐induced AKI. The mechanism by which 4‐PBA prevents tunicamycin‐induced kidney injury is currently under investigation. Supported by CIHR OSO‐115895.