Participation of Endoplasmic Reticulum Stress in the Pathogenesis of Spontaneous Glomerulosclerosis - Role of Intra-Renal Angiotensin System

ORIGINAL ARTICLE Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system Q3 MOHAMMAD A. AMINZADEH, TADASHI SATO, and NOSRATOLA D. VAZIRI IRVINE, CALIF; AND SAGA, JAPAN Endoplasmic reticulum (ER) is the site of synthesis, folding, assembly, and degrada- tion of proteins. Disruption of ER function leads to ER stress, which is marked by accu- mulation of unfolded proteins in the ER lumen. Detection of unfolded proteins by the ER membrane receptors triggers the ‘‘unfolded protein response (UPR)’’ designed to restore ER function via activation of the adaptive/cytoprotective responses. Failure of UPR or persistent stress triggers activation of ER stress-mediated apoptotic pathway. Several in vivo and in vitro studies have demonstrated the association of ER stress with glomerular diseases. Imai rats develop progressive glomerulosclerosis (GS), which is associated with oxidative stress, inflammation and activation of intra-renal angioten- sin system, and can be prevented by AT-1 receptor blockade (ARB). Since persistent oxidative and inflammatory stresses trigger ER stress-induced apoptosis and tissue in- jury, we hypothesized that kidneys in the Imai rats may exhibit failure of the adaptive and activation of the apoptotic ER stress responses, which could be prevented by ARB. To this end 10-week old Imai rats were randomized to untreated and ARB- treated groups and observed for 24 weeks. At age 34 weeks, untreated rats showed heavy proteinuria, azotemia, advanced GS, impaired ER stress adaptive/cytopro- tective responses (depletion of UPR-mediating proteins), and activation of ER stress apoptotic responses. ARB treatment attenuated GS, suppressed intra-renal oxidative stress, restored ER-associated adaptive/cytoprotective system, and prevented the ER stress mediated apoptotic response in this model. Thus, progressive GS in Imai rats is accompanied by activation of ER stress-associated apoptosis, which can be prevented by ARB. (Translational Research 2012;-:1–10) Abbreviations: ER ¼ endoplasmic reticulum; UPR ¼ unfolded protein response; GS ¼ glomerulo- sclerosis; AT-1 ¼ angiotensin II receptor type1; ARB ¼ angiotensin receptor-1 blockade; GRP94 ¼ glucose-regulated protein 94; GRP78 ¼ glucose-regulated protein 78, GRP78 also known as BiP; PERK ¼ double stranded RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase; ATF6 ¼ activating transcription factor 6; IRE1 ¼ inositol-requiring enzyme 1; eIF2a ¼ eukaryotic translation initiation factor-2a; XBP1 ¼ X-box-binding protein-1; Ask1 ¼ apoptosis-signal-regulat- ing kinase-1; NFkB ¼ nuclear factor kappa B; Bcl2 ¼ B-cell lymphoma 2 family of proteins; FSGS ¼ focal segmental glomerulosclerosis; Nrf2 ¼ nuclear factor-erythroid-2-related factor 2; BAX ¼ From the Division of Nephrology and Hypertension, University of California Irvine, Irvine, Calif; Department of Pediatrics, NHO Ureshino Medical Center, Saga, Japan. tension, The City Tower, Suite, 400, Orange, CA 92868; e-mail: ndvaziri@uci.edu. Submitted for publication December 6, 2011; revision submitted February 11, 2012; accepted for publication March 9, 2012. O 2012 Mosby, Inc. All rights reserved. 1931-5244/$ - see front matter doi:10.1016/j.trsl. 2012.03. 003 Reprint requests: Nosratola D. Vaziri, MD, MACP, University of California, Irvine Medical Center, Division of Nephrology and Hyper- FLA 5.1. 0 DTD TRSL561_proof 5 April 2012 9:07 pm ce