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  • Review Article
  • Published:

Proteostasis in endoplasmic reticulum—new mechanisms in kidney disease

Nature Reviews Nephrology volume 10, pages 369–378 (2014)Cite this article

Subjects

Key Points

  • Endoplasmic reticulum (ER) proteostasis is regulated by the adaptive unfolded protein response (UPR) pathway, which determines cell fate and maintains cell structure and function

  • Stress (hypoxia, inflammation and oxidative and glycative stress) disturbs ER proteostasis; cells subjected to long-term or severe ER stress are cleared via the apoptotic UPR pathway

  • In kidney cells, including glomerular cells, tubular cells and interstitial cells, derangement of ER proteostasis leads to development and progression of kidney diseases

  • Optimizing ER proteostasis using pharmacological approaches, such as small-molecule UPR modulators, might prove beneficial to prevent and treat kidney diseases

Abstract

Cells use an exquisite network of mechanisms to maintain the integrity and functionality of their protein components. In the endoplasmic reticulum (ER), these networks of protein homeostasis—referred to as proteostasis—regulate protein synthesis, folding and degradation via the unfolded protein response (UPR) pathway. The UPR pathway has two components: the adaptive UPR pathway, which predominantly maintains the ER function or ER proteostasis, and the apoptotic UPR pathway, which eliminates dysfunctional cells that have been subject to long-term or severe ER stress. Dysregulation of the UPR pathway often occurs in glomerular or tubulointerstitial cells under a pathogenic microenvironment, such as oxidative stress, glycative stress or hypoxia. A defective UPR is highly deleterious to renal cell function and viability and is thereby implicated in the pathophysiology of various kidney diseases. Accumulating evidence provides a link between the UPR pathway and mitochondrial structure and function, indicating the important role of ER proteostasis in the maintenance of mitochondrial homeostasis. Restoration of normal proteostasis, therefore, holds promise in protecting the kidney from pathogenic stresses as well as ageing. This Review is focused on the role of the ER stress and UPR pathway in the maintenance of ER proteostasis, and highlights the involvement of the derangement of ER proteostasis and ER stress in various pathogenic stress signals in the kidney.

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Figure 1: UPR pathway in ER proteostasis.
Figure 2: Proteostasis networks in the ER.
Figure 3: ER proteostasis in kidney disease.

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Acknowledgements

The authors' research work is supported by Grants-in-Aid for Scientific Research No. 25461207 (to R.I.) and 24390213 (to M.N.) from the Japan Society for the Promotion of Science, by the Japanese Association of Dialysis Physicians (JADP Grant 2012-05 to R.I.) and by Kyowa Hakko Kirin Pharmaceutical Company in Japan (to R.I.).

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Authors and Affiliations

  1. Division of Chronic Kidney Disease Pathophysiology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Reiko Inagi

  2. Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yu Ishimoto & Masaomi Nangaku

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  1. Reiko Inagi
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  2. Yu Ishimoto
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R.I. and Y.I. researched the data for the article and wrote the manuscript. All authors contributed to the discussion of the article's content and edited the manuscript before submission.

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Correspondence to Reiko Inagi.

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Inagi, R., Ishimoto, Y. & Nangaku, M. Proteostasis in endoplasmic reticulum—new mechanisms in kidney disease. Nat Rev Nephrol 10, 369–378 (2014). https://doi.org/10.1038/nrneph.2014.67

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