Abstract
Purpose of Review
Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN.
Recent Findings
As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR.
Summary
These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN.
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Acknowledgements
Y.F. is supported by National Natural Science Foundation of China (81400735) and Chinese Medical Association Funding (15020140602). K.L. is supported by NIH P30 DK079307 and 1R01DK098126. N.W. is supported by National Natural Science Foundation of China (81270824, 81670657). J.C.H. is supported by NIH 1R01DK109683, 1R01DK078897, 1R01DK088541, and P01-DK-56492.
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Ying Fan, Kyung Lee, Niansong Wang, and John Cijiang He declare that they have no conflict of interest.
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Fan, Y., Lee, K., Wang, N. et al. The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy. Curr Diab Rep 17, 17 (2017). https://doi.org/10.1007/s11892-017-0842-y
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DOI: https://doi.org/10.1007/s11892-017-0842-y