Bisphenol A aggravates renal ischemia–reperfusion injury by disrupting mitochondrial homeostasis and N‐acetylcysteine mitigates the injurious outcomes

Abstract

Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia–reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long‐term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N‐acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45‐min ischemia followed by 24‐hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA‐exposed rats that encountered RIR episode showed dose‐dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle‐exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP‐activated protein kinase (AMPK), PGC‐1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin‐related protein 1 (p‐DRP1)/Dynamin‐related protein 1 (DRP1), PTEN‐induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK‐PGC‐1α‐SIRT3 axis.

Roxadustat (FG‐4592) protects against ischaemia/reperfusion‐induced acute kidney injury through inhibiting the mitochondrial damage pathway in mice

“…26 Although, these treatments have failed to reduce the mortality rate of AKI worldwide. 27 Prevention of AKI is currently receiving increased attention.…”

The Role of Sirtuins in Kidney Diseases

“…SIRT3 overexpression was found to confer renal protection via the suppression of superoxide generation [ 84 ]. Reduced expression of SIRT3 was associated with increased severity of I/R-induced kidney injury, while restoration of SIRT3 reversed this damage by modulating mitochondrial homeostasis through the AMPK/PGC-1α pathway [ 85 ]. A recent study reported that SIRT5 was highly expressed in both the mitochondria and peroxisomes of proximal tubular cells, but the opposite trend was observed in I/R-induced kidney injury compared to other types of sirtuins, as the loss of SIRT5 function led to renoprotective effects after I/R injury; shifting of fatty acid oxidation from the mitochondria to the peroxisome under the control of SIRT5 was suggested as the underlying mechanism.…”

Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A

“…Detection of protein was performed using Bio-Rad’s Clarity ECL Western Blot Substrate kits and the blot bands were developed in ChemiDoc Touch Imaging System (Bio-Rad Laboratories, Inc., Philadelphia, PA, USA). Analysis of protein expression was determined by the Image J program [ 21 ]. Each protein expression was normalized with β-actin expression.…”