Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis-Role of intra-renal angiotensin system

Endoplasmic reticulum (ER) is the site of synthesis, folding, assembly, and degradation of proteins. Disruption of ER function leads to ER stress, which is marked by accumulation 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 angiotensin system, and can be prevented by AT-1 receptor blockade (ARB). Since persistent oxidative and inflammatory stresses trigger ER stress-induced apoptosis and tissue injury, 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/cytoprotective responses (depletion of UPR-mediating proteins), and activation of ER stress apoptotic responses. ARB treatment attenuated GS, suppressed intro-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;160:309-318)