1. Volume 84, Issue 1, Pages 25-33 (July 2013)
The intersecting roles of endoplasmic reticulum stress, ubiquitin–proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease 
Andrey V. Cybulsky 
Kidney International 
Volume 84, Issue 1, Pages (July 2013)
DOI: /ki
Copyright © 2013 International Society of Nephrology Terms and Conditions

2. Figure 1
Endoplasmic reticulum (ER) stress pathways and responses. Early, ‘adaptive’ unfolded protein response (UPR) inhibits translation and attenuates protein synthesis at the ER via protein kinase RNA-like ER kinase (PERK)–mediated phosphorylation of eukaryotic translation initiator factor 2α (eIF2α), and activation of mRNA decay by regulated inositol-requiring protein 1α (IRE1α)–dependent decay (RIDD). Activating transcription factor 6 cytosolic fragment (ATF6n), IRE1-α, and spliced X box–binding protein 1 (Xbp1s) induce UPR and ER-associated degradation (ERAD) genes that work to restore ER function and maintain cell survival. Prolonged, intense ER stress is cytotoxic; sustained PERK signaling upregulates the pro-apoptotic transcription factor C/EBP-homologous protein (CHOP). IRE1α also sensitizes cells to apoptosis through activation of c-Jun N-terminal kinase (JNK), and RIDD of mRNAs that encode for chaperones. Activation of autophagy through the IRE1α/JNK or PERK pathways may be adaptive or cytotoxic. Dashed arrows show transition from adaptive to cytotoxic responses. Atg12, autophagy-related gene 12.
Kidney International  , 25-33DOI: ( /ki )
Copyright © 2013 International Society of Nephrology Terms and Conditions

3. Figure 2
The ubiquitin–proteasome system (UPS) and endoplasmic reticulum–associated degradation (ERAD): effects of complement C5b-9. In the cytosol, or at the cytosolic face of the endoplasmic reticulum (ER), ubiquitin (Ub) is attached to a misfolded protein or a protein with a degradation signal through an enzymatic cascade involving E1, E2, and E3 enzymes. After attachment of at least four ubiquitin moieties, the substrate is targeted to the 26S proteasome. Unfolding and deubiquitination of the substrate take place before degradation in the interior chamber. In the ER, misfolded proteins are deglycosylated by enzymes such as ER mannosidase I (Man I), and interact with ER-associated degradation (ERAD)-enhancing α-mannosidase-like protein 1 (EDEM) and other ERAD lectins. Substrates are then retrotranslocated out of the ER and in the process undergo ubiquitination, followed by proteasomal degradation. In C5b-9-mediated glomerular epithelial cell injury, there is increased polyubiquitinated protein. Nevertheless, complement enhances global UPS function. Mechanisms may involve enhanced conjugation/ligation of ubiquitin, or changes in unfolding and deubiquitination. Complement also impairs ERAD. Mechanisms may include an increase in the amount of misfolded proteins competing for ER-resident enzymes and ER chaperones, or dysregulation of the ERAD pathway inside the ER or at retrotranslocation.
Kidney International  , 25-33DOI: ( /ki )
Copyright © 2013 International Society of Nephrology Terms and Conditions

4. Figure 3
Podocytes in normal human kidney and human membranous nephropathy. (a) Normal podocyte ultrastructure. The cell body shows a few narrow cisternae of the endoplasmic reticulum (ER). (b–d) Cases of membranous nephropathy. Podocyte cell bodies show expanded and dilated ER. In d, dilatation is extreme, and the ER resembles a labyrinth of extended cisternae. The changes are compatible with ER stress. The electron micrographs were provided by Dr Dontscho Kerjaschki.
Kidney International  , 25-33DOI: ( /ki )
Copyright © 2013 International Society of Nephrology Terms and Conditions