Endoplasmic Reticulum: The Master Regulator of Stress Responses in Glomerular Diseases (2011)

The glomerulus is composed of glomerular resident cells, which include podocytes, mesangial cells, and glomerular endothelial cells, and is response for glomerular filtration. A range of pathogenic conditions can cause structural and functional damage to these glomerular cells, including hypertension, diabetes, and inflammation; these induce glomerulonephritis, which in turn leads to end-stage renal failure. Extensive investigations have uncovered the molecular mechanisms by which glomerulonephritis progresses, including the contribution of cellular stress signals induced by oxidative stress, hypoxia, or inflammation. The endoplasmic reticulum (ER) is an organelle that maintains protein homeostasis, which includes regulation of the concentration, conformation, folding, and trafficking of client proteins. ER dysfunction causes an imbalance between protein-folding capacity and proteinfolding load, a condition referred to as ER stress. This stress triggers the accumulation of unfolded proteins in the ER and subsequent activation of an intracellular stress signal, the unfolded protein response (UPR). ER stress and the UPR can result from various disturbances, such as hypoxia, glucose deprivation, and oxidative stress. The UPR, which initially serves as an adaptive response to maintain the homeostasis of the ER, induces ER resident chaperones, which act to enhance protein-folding capacity, the activation of pathways that degrade unfolded proteins accumulated in the ER (ERAD), and the attenuation of translation. The physiological level of the UPR transformes to a pathogenic response when ER stress is overwhelming or prolonged. At its pathogenic level, the UPR produces an apoptotic response, namely the activation of UPR-related proapoptotic molecules and inhibition of anti-apoptotic molecules. Accumulating evidence demonstrates that ER stress contributes not only to protein conformational diseases, but also to the progression of various diseases, including cardiac disease, diabetes, cancer, and kidney disease. Given the linkage of ER stress with oxidative stress or hypoxia, both of which are pathogenic, it is hardly surprising that the potential pathophysiological significance of ER stress is evoked across a wide range of diseases. Recent evidence demonstrates that ER stress is a significant contributor to glomerulonephritis. Podocytes play an important role in the glomerular filtration barrier that is maintained by filtration slits (slit diaphragm), and express various proteins associated www.intechopen.com An Update on Glomerulopathies -Etiology and Pathogenesis 248 with the slit diaphragm. Congenital nephrotic syndrome is caused by genetic mutation of slit diaphragm-associated molecules, such as nephrin and -actinin-4. These mutated proteins are malfolded and accumulated in the ER of podocytes, and thereby induce the UPR, namely ER chaperone expression and proapoptotic gene induction. Mesangial cells are responsible for the structural and functional maintenance of glomerular tufts and mesangial cell damage in glomerulonephritis is associated with induction of the UPR, which involves ER chaperone expression and the attenuation of protein translation. The induction level of the UPR increases in parallel with disease progression. These data suggest that the UPR maintains ER homeostasis in glomerular cells and ensures cell survival under pathogenic conditions. ER stress pathophysiologically contributes to tubulointerstitial damage not only in glomeruli, but also tubules. Tubular damage, such as tubular cell death caused by proteinuria, ischemia-reperfusion, or nephrotoxin, predominantly enhances the UPR, especially UPR-induced apoptosis and autophagy. These findings emphasize not only the importance of ER stress as a new progression factor but also the interesting future possibility of renoprotective strategies which target ER stress. In experimental glomerular and tubular injury model animals, overexpression of GRP78 (glucose-regulated protein 78), a master regulator of UPR, or administration of the chemical compounds that regulate UPR activation shows renoprotective effects. Preconditioning of ER stress with non-nephrotoxic dose of ER stress inducers protects against the podocyte and mesangial cell damage they induced. Interestingly, some oxidative stress inhibitors and advanced glycation inhibitors also act as UPR inhibitors, suggesting a link between oxidative stress, hypoxia, and ER stress. Therapeutic approaches which target ER stress may act by breaking the vicious cycle of this stress signal crosstalk in kidney disease. Here, I summarize the role of ER stress as the master regulator of the stress response in glomerular disease and the therapeutic possibility of targeting UPR molecules.