The intersecting roles of endoplasmic reticulum stress, ubiquitin- proteasome system, and autophagy in the pathogenesis of proteinuric kidney disease.
Protein misfolding in the endoplasmic reticulum (ER) leads to ER stress. The unfolded protein response and ER-associated degradation (ERAD) interact in a coordinated manner with the ubiquitin-proteasome system and autophagy to alleviate protein misfolding or its consequences. The intersecting actions of these processes are evident in normal podocyte physiology, and in proteinuric glomerular diseases, including experimental membranous nephropathy, focal segmental sclerosis, and diabetic nephropathy. There is some evidence for the induction of ER stress, changes in the ubiquitin-proteasome system, and presence of autophagy in human glomerulopathies. Various therapeutic approaches to the unfolded protein response, ERAD, and the ubiquitin-proteasome system have corrected experimental glomerular diseases involving protein misfolding, and could potentially be developed as therapies in humans.Kidney International advance online publication, 19 December 2012; doi:10.1038/ki.2012.390.