Endoplasmic reticulum-mediated organelle crosstalk in kidney disease

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.