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/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 a a by the protein synthesis slows the translation rate, thereby reducing the protein load on the ER. Active ATF6 migrates to the Golgi apparatus where it is cleaved and then activated by limited prote- olysis. Cleaved ATF6 then migrates to the nucleus to promote transcription of ER chaperones and XBP1. XBP1 mRNA is subsequently spliced by active IRE1 and thereby achieves its active form sXBP1. The sXBP1, in turn, works in parallel with ATF6 to promote gene transcription of ER enzymes, chaperons, PERK-inhibitor, P58IPK, and genes involved in protein degradation. In an attempt to restore the ER function and maintainthe redox homeo- stasis, PERK also phosphorylates Nrf2, which is the master regulator of genes encoding many antioxidant and phase II detoxifying enzymes. Upon phosphorylation, Nrf2 dissociates from Nrf2-Keap1 complex, enters the nu- cleus and binds to antioxidant responsive elements (ARE) in the promoter regions of the target genes. Prolonged stress or failure of adaptive/cytoprotective responses of ER stress leads to switch of the signals from prosurvival to proapoptotic and activation of apoptotic responses of ER stress. IRE1 recruits ASK1 that relays stress signals to downstream MAP kinases including c-Jun N-terminal kinase (JNK). IRE1 can also activate NF k B that can accentuate ER stress-associated tissue damage and inﬂammation.