Endoplasmic Reticulum Calcium Homeostasis in Kidney Disease

Abstract

Calcium (Ca 2þ ) homeostasis is a crucial determinant of cellular function and survival. Endoplasmic reticulum (ER) acts as the largest intracellular Ca 2þ store that maintains Ca 2þ homeostasis through the ER Ca 2þ uptake pump, sarco/ER Ca 2þ ATPase, ER Ca 2þ release channels, inositol 1,4,5-trisphosphate receptor channel, ryanodine receptor, and Ca 2þ -binding proteins inside of the ER lumen. Alterations in ER homeostasis trigger ER Ca 2þ depletion and ER stress, which have been associated with the development of a variety of diseases. In addition, recent studies have highlighted the role of ER Ca 2þ imbalance caused by dysfunction of sarco/ER Ca 2þ ATPase, ryanodine receptor, and inositol 1,4,5trisphosphate receptor channel in various kidney diseases. Despite progress in the understanding of the importance of these ER Ca 2þ channels, pumps, and binding proteins in the pathogenesis of kidney disease, treatment is still lacking. This mini-review is focused on: i) Ca 2þ homeostasis in the ER, ii) ER Ca 2þ dyshomeostasis and apoptosis, and iii) altered ER Ca 2þ homeostasis in kidney disease, including podocytopathy, diabetic nephropathy, albuminuria, autosomal dominant polycystic kidney disease, and ischemia/reperfusion-induced acute kidney injury.

Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease

“…The ER Ca 2+ homeostasis is mainly controlled by two Ca 2+ releasing channels, inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR), and one Ca 2+ reuptake channel, sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA). Dysfunctions of these ER Ca 2+ channels cause a variety of kidney diseases, including ischemia/reperfusion (I/R)-induced tubular injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy [24]. It is reported that I/R induces renal tubule apoptosis when activation of IP3R starts a cascade of Ca 2+ release from the ER store [25].…”

Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases

“…Most secreted proteins, transmembrane proteins, and lipids are produced in the ER. In addition, the ER maintains cellular homeostasis by tightly regulating calcium dynamics, phospholipid biogenesis, and various intracellular signals by releasing Ca 2+ (Chevet et al 2001 ; Berridge 2002 ; Park et al 2021 ). Alterations in calcium levels and metabolism, redox imbalances, nutrient deprivation, and hypoxia can disrupt ER homeostasis (Schonthal 2012 ).…”

1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic Acid Acetoxymethyl Ester Loaded Reactive Oxygen Species Responsive Hyaluronic Acid–Bilirubin Nanoparticles for Acute Kidney Injury Therapy via Alleviating Calcium Overload Mediated Endoplasmic Reticulum Stress

“…14 Sustained ER stress further induces large amounts of Ca 2+ to be rapidly released from calcium pools, disrupting the ER calcium balance and resulting in severe [Ca 2+ ] i dysregulation. 15 Reduced ER luminal Ca 2+ could exacerbate ER stress and apoptosis by disrupting calciumdependent chaperone functions and accumulating unfolded proteins, resulting in renal cell apoptosis, which exacerbates tissue injury. 16 (3) Dysfunction of cellular energy metabolism: The rapid degradation and massive consumption of ATP supply, loss of mitochondrial function caused by overproduction of ROS, and subsequent reduced ATP production all combine to overwhelm the cell's ability to maintain overall homeostasis and contribute to renal cell injury.…”

“…Concrete mechanisms of kidney cell damage in the pathological process of AKI could include the following: (1) Intracellular Ca 2+ overload: During renal ischemia and hypoxia, the initial decrease in ATP causes depolarization of the cell membrane and activates the intracellular Na + –Ca 2+ exchange mechanism, which results in a massive extracellular Ca 2+ influx through the Ca 2+ channel. , (2) Oxidative stress injury: ATP is extensively degraded to hypoxanthine during renal ischemia and hypoxia, and hypoxanthine can further react with increased oxygen molecules during reperfusion, fueling the generation of massive amounts of reactive oxygen species (ROS). , Excessive ROS can not only damage organelle and plasma membranes, accelerating Ca 2+ influx via transmembrane ion transport perturbations, but also severely damage the structural functions of mitochondria and the endoplasmic reticulum (ER) . Sustained ER stress further induces large amounts of Ca 2+ to be rapidly released from calcium pools, disrupting the ER calcium balance and resulting in severe [Ca 2+ ] i dysregulation . Reduced ER luminal Ca 2+ could exacerbate ER stress and apoptosis by disrupting calcium-dependent chaperone functions and accumulating unfolded proteins, resulting in renal cell apoptosis, which exacerbates tissue injury .…”