Abstract
Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.
Highlights
Diabetic kidney disease (DKD) is the most common worldwide cause of chronic kidney disease and a growing public health challenge [1]
We recently demonstrated that constitutive knockout of TRB3 worsens albuminuria, cytokine and chemokine expression in murine Type 1 diabetic kidney disease [107], supporting the protective effects of endoplasmic reticulum (ER) stress
Hartleben and colleagues elegantly demonstrated that podocyte-specific deletion of autophagy-related 5 (Atg5) leads to glomerulopathy in aging mice and this was associated with ER stress, podocyte loss, proteinuria and glomerulosclerosis [143]. Mammalian Target of Rapamycin (mTOR) closely regulates autophagy, further supporting the tight interconnections among ER stress, mTOR and autophagy pathways [159,160]
Summary
Diabetic kidney disease (DKD) is the most common worldwide cause of chronic kidney disease and a growing public health challenge [1]. Subsequent work revealed that increases in the load of unfolded proteins in the ER, activates a complex signaling pathway—the unfolded protein response (UPR). When the cell becomes overwhelmed by misfolded proteins, it is considered the ER stress response. It is unclear when cells cross the line between the UPR and ER stress; Rutkowski and Hedge have suggested that ER stress occurs when the ER functions in an environment that lies outside of its normal physiological range. A number of factors activate the UPR including nutrient excess and deprivation, altered protein glycosylation, reducing agents, changes in ER calcium content, oxidative stress and TLR signaling. Our understanding of microRNAs and their impact on the UPR remains rudimentary
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