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Endoplasmic reticulum-mediated organelle crosstalk in kidney disease

Nature Reviews Nephrology (2025)Cite this article

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Abstract

The endoplasmic reticulum (ER) is a key organelle involved in a wide range of intracellular biological processes, including Ca2+ homeostasis; lipid metabolism; proteostasis through protein synthesis, folding and processing of secretory and transmembrane proteins; and signal transduction. The ER forms extensive physical interactions with various intracellular organelles through the membrane contact sites, enabling direct exchange of ions and lipids without vesicular transport. At mitochondria-associated membranes, ER–mitochondria communication governs calcium transfer, lipid synthesis, mitochondrial dynamics, the unfolded protein response and inflammation, all of which are essential for maintaining cellular homeostasis. The ER also interacts with the Golgi apparatus, endosomes and plasma membrane to facilitate transfer of calcium and lipids. Disruption of ER–organelle communication contributes to the development and progression of various kidney diseases, including diabetic kidney disease, acute kidney injury and polycystic kidney disease. Accordingly, ER–organelle communication has emerged as a promising therapeutic target. Pharmacological agents such as SGLT2 inhibitors, AMPK activators, mTOR inhibitors and RAAS blockers have been shown to restore ER–mitochondria communication and alleviate kidney injury in experimental models. Advancing our understanding of ER–organelle crosstalk may offer new mechanistic insights and contribute to the optimization of current treatment strategies for kidney disease.

Key points

  • The endoplasmic reticulum (ER) forms extensive membrane contact sites with other intracellular organelles and acts as a central hub for inter-organelle communication.

  • Mitochondria-associated membrane proteins at ER–mitochondria interfaces coordinate Ca2+ homeostasis; lipid metabolism; ER stress responses; mitochondrial dynamics including mitochondrial fusion, fission and mitophagy; and inflammatory responses, which are essential for maintaining cellular homeostasis.

  • ER communication with late endosomes and/or lysosomes, the Golgi apparatus and the plasma membrane primarily regulates intracellular Ca2+ homeostasis and non-vesicular lipid transport.

  • Therapeutic targeting of ER–organelle communication may resolve upstream dysfunctions such as Ca2+ imbalance, mitochondrial damage and ER stress, offering new opportunities for kidney disease treatment.

  • Pharmacological agents such as SGLT2 inhibitors, AMPK activators, mTOR inhibitors and RAAS inhibitors may exert nephroprotective effects by modulating ER–organelle communication.

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Fig. 1: Roles of endoplasmic reticulum–mitochondria communication in calcium transfer and lipid homeostasis.
Fig. 2: Roles of endoplasmic reticulum–mitochondrial communication in mitochondrial homeostasis, the unfolded protein response and inflammation.
Fig. 3: Communication between the endoplasmic reticulum and late endosomes or lysosomes.
Fig. 4: Communication between the endoplasmic reticulum and the Golgi apparatus.
Fig. 5: Communication between the endoplasmic reticulum and the plasma membrane.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Yu Ah Hong  (홍유아)

  2. Division of Chronic Kidney Disease Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

    Yu Ah Hong  (홍유아) & Reiko Inagi  (稲城玲子)

Authors
  1. Yu Ah Hong  (홍유아)
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  2. Reiko Inagi  (稲城玲子)
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Y.A.H. researched data for the article and wrote the manuscript. Both authors discussed the content and reviewed and edited the manuscript before submission.

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Correspondence to Reiko Inagi  (稲城玲子).

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Nature Reviews Nephrology thanks Richard Austin, Alessia Fornoni, who co-reviewed with Rachel Njeim, and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Hong, Y.A., Inagi, R. Endoplasmic reticulum-mediated organelle crosstalk in kidney disease. Nat Rev Nephrol (2025). https://doi.org/10.1038/s41581-025-00989-4

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