Prohibitin Attenuates Oxidative Stress and Extracellular Matrix Accumulation in Renal Interstitial Fibrosis Disease

Tian-Biao Zhou,Feng-Ying Lei,Gregor P C Drummen,Wei-Fang Huang,Yuan-Han Qin,Christos Chatziantoniou

doi:10.1371/journal.pone.0077187

Abstract

Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Both prohibitin over- and under-expression have been implicated in various diseases and cell types. We recently demonstrated that prohibitin down-regulation results in increased renal interstitial fibrosis (RIF). Here we investigated the role of oxidative stress and prohibitin expression in RIF in unilateral ureteral obstructed rats. Lentivirus-based delivery vectors were used to knockdown or over-express prohibitin. Our results show that increased prohibitin expression was negatively correlated with the RIF index, reactive oxygen species, malon dialdehyde, transforming growth factor β1, collagen IV, fibronectin, and cell apoptosis index. In conclusion, we postulate that prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.

Highlights

Renal interstitial fibrosis (RIF) is characterized by the extensive and progressive accumulation of extracellular matrix (ECM) [1,2]
The rats were randomly divided into five groups: (i) sham operation group (SHO); control group that underwent exactly the same surgical procedure as the experimental group, without the treatment under study, (ii) model group subjected to unilateral ureteral obstruction (UUO), (iii) UUO rats treated with lentivirus carrying PHB-siRNA (PHB2), (iv) UUO rats treated with lentivirus carrying Phb (PHB+), and (v) UUO rats treated with control viruses, n = 10, respectively
Since unilateral ureteral obstruction (UUO) is a well-characterized model for experimental obstructive nephropathy [28], which causes amongst others oxidative stress and culminates in renal tubular apoptosis and interstitial fibrosis [29,30,31,32], we opted to perform our experiments in lab animals

Summary

Introduction

Renal interstitial fibrosis (RIF) is characterized by the extensive and progressive accumulation of extracellular matrix (ECM) [1,2]. Interstitial fibrosis is the primary morphologic predictor of clinical outcome and is tightly linked to disease progression [4,5]. The PHB content is inversely associated with cell proliferation, but distinctly increases during granulosa cell differentiation as well as in earlier events of apoptosis in a temperature-sensitive granulosa cell line [9]. Gene interference with PHB–siRNA showed a heightened sensitivity to anthralinmediated cell death due to enhanced loss of mitochondrial membrane potential [10]. This suggests that PHB might have a protective function against apoptosis. Increased PHB levels in response to subtle caloric restriction indicate that such an increase may be one of the early events leading to lifespan expansion in response to caloric restriction [11]

Methods

Results

Conclusion