Endoplasmic reticulum stress in proteinuric kidney disease

Endoplasmic reticulum (ER) stress refers to physiological or pathological states that result in accumulation of misfolded proteins in the ER. To handle misfolded proteins, the ER has in place quality control mechanisms, including the unfolded protein response and ER-associated degradation (ERAD). ER stress in renal pathophysiology is a relatively new area of research. Mice heterozygous for a mutation in the ER chaperone, BiP, develop glomerulosclerosis and tubulointerstitial disease. Induction of ER stress in glomerular cells has been described in experimental models of membranous nephropathy and membranoproliferative glomerulonephritis, and exogenous induction of ER stress ('preconditioning') reduced proteinuria. In human kidney biopsies, markers of ER stress in glomeruli have been identified in various noninflammatory and inflammatory glomerulopathies. A tubulointerstitial ER stress response, in some cases associated with tubular cell apoptosis, may occur in glomerular diseases associated with proteinuria, including puromycin aminonucleoside nephrosis, protein overload, and experimental and human diabetic nephropathy. Certain missense mutations in nephrin and podocin, as well as underglycosylation of nephrin, result in misfolding and retention in the ER, and eventually ERAD. Understanding the various aspects of ER stress will provide an opportunity for development of novel therapeutic strategies for proteinuric diseases. Kidney International (2010) 77, 187-193; doi:10.1038/ki.2009.389; published online 7 October 2009