Endoplasmic Reticulum: The Master Regulator of Stress Responses in Glomerular Diseases

The intersecting roles of endoplasmic reticulum stress, ubiquitin–proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease

“…Subsequent development of glomerulosclerosis, foot process effacement, and loss of podocytes was evident in Atg5-knockout animals, suggesting that autophagy defends the integrity of podocytes during glomerular injury. 44 An earlier study showed a decrease in LC3 in podocytes after administration of puromycin aminonucleoside to rats, and an increase in LC3 during the recovery phase of nephrosis, 43 whereas other studies have shown the induction of glomerular ER stress after administration of puromycin aminonucleoside, 12 suggesting a link of ER stress with autophagy in this disease model. The results support the view that autophagy is a recovery mechanism, although the functional role of ER stress and the causal connection between ER stress and autophagy in this model need to be established.…”

“…Among the first observations of ER stress in glomerulopathies were studies of experimental membranous nephropathy, which showed the activation of an adaptive UPR by the complement C5b-9 membrane attack complex in podocytes, both in culture and in the passive Heymann nephritis model in vivo. 11,12 Studies in cultured glomerular epithelial cells showed that UPR induction was associated with a perturbation of the ER membrane by complement, which could induce dysregulation of ER calcium content, thereby disrupting protein folding in the ER. Other factors contributing to protein misfolding in cells exposed to complement could include ATP depletion or altered redox balance.…”

“…11 In summary, both the UPR and UPS were shown to have protective roles in cell culture models of complementmediated podocyte injury, and there is also evidence for their protective roles in vivo (experimental membranous nephropathy). 11,12,37 Induction of ER stress resulted in the upregulation of autophagy markers in cultured podocytes; 45 nevertheless, establishing a cause-and-effect relationship of the two processes in vivo requires further study. The development of experimental mouse models involving genetic deletion of UPR sensors in podocytes would conceivably facilitate better characterization of the individual UPR pathways in glomerular injury.…”

“…Deletion of Atg5 also exacerbated podocyte injury after administration of puromycin aminonucleoside or adriamycin, suggesting that autophagy may limit podocyte injury in experimental focal segmental sclerosis or minimal change disease. 44 Moreover, ER stress markers have been demonstrated in experimental models of focal segmental sclerosis, 12 although causal interactions of ER stress and autophagy remain to be established. Most of the knowledge has been derived from work carried out in experimental models, and it will be necessary to validate the key experimental observations in human disease.…”

“…[4][5][6] The roles of ER stress and autophagy in renal pathophysiology are increasingly appreciated, and a number of comprehensive reviews have been published. [7][8][9][10][11][12][13][14][15][16] The present mini review focuses on the intersecting actions of the UPR, ERAD, UPS, and autophagy in glomerular pathophysiology, and highlights developments in these areas since a previous mini review in this journal in 2010. 11…”