Oxalate, a non-essential end product of metabolism, causes hyperoxaluria and eventually calcium oxalate (CaOx) stone disease. Kidney cells exposed to oxalate stress results in generation of reactive oxygen species (ROS) and progression of stone formation. Perturbations in endoplasmic reticulum (ER) result in accumulation of misfolded proteins and Ca(2+) ions homeostasis imbalance and serve as a common pathway for various diseases, including kidney disorders. ER stress induces up-regulation of pro-survival protein glucose-regulated protein 78 (GRP78) and pro-apoptotic signaling protein C/EBP homologous protein (CHOP). Since the association of oxalate toxicity and ER stress on renal cell damage is uncertain, the present study is an attempt to elucidate the interaction of GRP78 with oxalate by computational analysis and study the role of ER stress in oxalate-mediated apoptosis in vitro and in vivo. Molecular docking results showed that GRP78-oxalate/CaOx interaction takes place. Oxalate stress significantly up-regulated expression of ER stress markers GRP78 and CHOP both in vitro and in vivo. Exposure of oxalate increased ROS generation and altered antioxidant enzyme activities. N-Acetyl cysteine treatment significantly ameliorated oxalate-mediated oxidative stress and moderately attenuated ER stress marker expression. The result indicates oxalate toxicity initiated oxidative stress-induced ER stress and also activating ER stress mediated apoptosis directly. In addition, the up-regulation of transforming growth factor β-1 revealed oxalate may induce kidney fibrosis through ER stress-mediated mechanisms. The present study provide insights into the pathogenic role of oxidative and ER stress by oxalate exposure in the formation of calcium oxalate stone.
Journal of physiology and biochemistry. 2017 Sep 05 [Epub ahead of print]
Albert Abhishek, Shaly Benita, Monika Kumari, Divya Ganesan, Eldho Paul, Ponnusamy Sasikumar, Ayyavu Mahesh, Subramani Yuvaraj, Tharmarajan Ramprasath, Govindan Sadasivam Selvam
Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India., Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA., DBT-IPLS Programme, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India., Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA., Department of Biochemistry, Centre for Excellence in Genomics Science, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India. .