Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway.

Meei-Ling Sheu,Chin-Chang Shen,Chih-Kang Chiang,Yuan-Siao Chen

doi:10.18632/oncotarget.14270

Abstract

Ochratoxin A (OTA) contaminated food increases reactive oxygen species (ROS) production in glomerulus and causes glomerulopathy. The molecular mechanisms still remain uncertain. In this study, we used mouse and rat glomerular mesangial cells and delineate the signaling pathway behind the OTA-triggered cell apoptosis. OTA dose-dependently induced expression of ER stress markers including phospho-PERK, phospho-eIF2α, GRP78, GRP94, and CHOP. Apoptosis events including cleavage of caspase-12, caspase-7, and PARP are also observed. OTA activated oxidative stress and increased NADPH oxidase activity. NADPH oxidase inhibitor, apocynin, significantly attenuated OTA-induced cell apoptosis. Moreover, OTA markedly increased the calpain activity which significantly inhibited by apocynin. Transfection of calpain-siRNA effectively inhibited the OTA-increased ER stress-related protein expression. These findings suggest that OTA activated NADPH oxidase and calpain, induced ER stress and ROS production, and caused glomerular mesangial cells apoptosis which leads to glomerulopathy.

Highlights

Ochratoxin A (OTA), a widely-spread mycotoxin produced by fungi, is a contaminant in the food chain worldwide
Transfection of calpain-siRNA effectively inhibited the OTA-increased Endoplasmic reticulum (ER) stress-related protein expression. These findings suggest that OTA activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and calpain, induced ER stress and reactive oxygen species (ROS) production, and caused glomerular mesangial cells apoptosis which leads to glomerulopathy
It has been analyzed that the average weekly intake of OTA varies from 130 to 6489 ng in inhabitants from an area with high Balkan endemic nephropathy (BEN) incidence in Bulgaria [11,12]

Summary

Introduction

Ochratoxin A (OTA), a widely-spread mycotoxin produced by fungi, is a contaminant in the food chain worldwide. The pathological characterizations of BEN include a progressive atrophy and sclerosis in the kidney [2]. The glomerular and vascular lesions can be observed in BEN, which include ischemic, microcystic, and obsolescent glomeruli, occasional thrombotic microangiopathy-like lesions, and focal segmental sclerosis-like lesions [2]. The renal lesions in porcine nephropathy, which OTA is a major causal determinant, are characterized by the degeneration of the proximal tubules, interstitial fibrosis and hyalinization of the glomeruli [3]. The regional thickening and degeneration of the glomerular basement membrane has been found in broiler chicks fed OTA [4]. Ciarcia et al has shown that OTA treatment presented hypertension and reduction of glomerular filtration rate in rats [5]. The molecular mechanisms involved in the OTA-induced glomerulopathy still remain uncertain

Methods

Results

Conclusion