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Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases

Nature Reviews Nephrology volume 13, pages 681–696 (2017)Cite this article

Subjects

Key Points

  • Endoplasmic reticulum (ER) function and autophagy are essential for protein homeostasis (proteostasis) in podocytes

  • Protein misfolding and ER stress are evident in various renal diseases, including primary glomerulonephritides, glomerulopathies associated with genetic mutations, diabetic nephropathy, acute kidney injury, chronic kidney disease and renal fibrosis

  • The unfolded protein response might interact in a coordinated manner with autophagy to alleviate protein misfolding and its consequences in kidney diseases

  • Monitoring ER chaperone excretion in the urine can potentially serve as a biomarker of renal ER stress

  • Treatment with chemical chaperones that improve protein folding or chaperone inducers has alleviated kidney injury

  • Normalization of ER stress using pharmacological agents might be a promising therapeutic approach for preventing or arresting the progression of kidney disease

Abstract

Progress has been made in our understanding of the mechanisms of endoplasmic reticulum (ER) proteostasis, ER stress and the unfolded protein response (UPR), as well as ER stress-induced autophagy, in the kidney. Experimental models have revealed that disruption of the UPR, including a protein that senses misfolded proteins (namely, inositol-requiring enzyme 1α) in mouse podocytes causes podocyte injury and albuminuria as mice age. Protein misfolding and ER stress are evident in various renal diseases, including primary glomerulonephritides, glomerulopathies associated with genetic mutations, diabetic nephropathy, acute kidney injury, chronic kidney disease and renal fibrosis. The induction of ER stress may be cytoprotective, or it may be cytotoxic by activating apoptosis. The UPR may interact in a coordinated manner with autophagy to alleviate protein misfolding and its consequences. Monitoring the excretion of ER chaperones into the urine can potentially serve as a biomarker of renal ER stress. In specific kidney diseases, the treatment of experimental animals with chemical chaperones that improve protein folding or with chaperone inducers has alleviated kidney injury. Given the limited availability of mechanism-based therapies for kidney diseases, normalization of ER stress using pharmacological agents represents a promising therapeutic approach towards preventing or arresting the progression of kidney disease.

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Figure 1: Protein folding, quality control and unfolded protein response (UPR) activation in the endoplasmic reticulum (ER).
Figure 2: Control of autophagy by endoplasmic reticulum (ER) stress.
Figure 3: Abrogation of endoplasmic reticulum (ER) stress pathways leads to podocyte injury.
Figure 4: Urinary endoplasmic reticulum (ER) stress biomarkers for the diagnosis of glomerular disease.

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Acknowledgements

The author is supported by research grants from the Canadian Institutes of Health Research (MOP-125988 and MOP-133492) and the Catherine McLaughlin Hakim Chair.

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  1. Division of Nephrology, Department of Medicine, McGill University Health Centre Research Institute EM13238, 1001 Decarie Boulevard, Montreal, H4A 3J1, Quebec, Canada

    Andrey V. Cybulsky

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Cybulsky, A. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol 13, 681–696 (2017). https://doi.org/10.1038/nrneph.2017.129

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