4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression

Abstract

Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP−/− mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.

Structure–activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro

“…Values were normalized using β-actin and expressed as percentage of DMSO-treated control for GRP78 or percentage of TM-treated group for CHOP (mean ± SEM; n = 3) protects against TM-induced expression of both GRP78 and CHOP. However, a higher magnitude of reduction was observed on CHOP expression (Carlisle et al 2014). Our findings are in line with a previous study in HK-2 cells by Carlisle et al, where 4PBA has been shown to prevent TM-induced CHOP expression without affecting the expression of GRP78 (Carlisle et al 2014).…”

“…We compared the potency and efficacy of piperine and its analogs against 4-phenylbutyrate (4PBA), a well-known chemical chaperone, used at 1 and 2 mM concentrations (Carlisle et al 2014) (Fig. 2a-d).…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2008; Carlisle et al. 2014). Notably, tunicamycin‐induced acute kidney injury is blunted in CHOP knockout mice, or in mice treated with the chemical chaperone 4‐PBA (Marciniak et al.…”

“…2004; Carlisle et al. 2014). In liver, the lesions observed in tunicamycin‐intoxicated animals include steatosis, bile ductular hyperplasia, swollen hepatocytes, and the presence of apoptotic bodies (Finnie and O'Shea 1989; Finnie and O'Shea 1990b; Finnie et al.…”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…It has been reported that 4-PBA can suppress ER stress. 21, 22 Ozcan et al 20 found that both UDCA and 4-PBA alleviated ER stress, which resulted in the normalization of hyperglycemia and restoration of systemic insulin sensitivity, thereby revealing their potential benefits in the treatment of type 2 diabetes. Therefore, we hypothesize that UDCA and 4-PBA may prevent kidney damage in type 2 diabetic mellitus through the inhibition of ER stress.…”