Pathological role of the calcium‐sensing receptor in sepsis‐induced hypotensive shock: Therapeutic possibilities and unanswered questions

Abstract

Sepsis is a life-threatening disease involving multiorgan dysfunction, prompted by an unregulated host response to infection. Shock is a complication of sepsis in which the circulatory and cellular metabolism anomalies are significant enough to raise the risk of death. Calcium dyshomeostasis occurs during sepsis condition due to imbalance between calcium uptake and excessive release induced by inflammatory cytokines. This calcium imbalance can cause activation of calcium-sensing receptors (CaSRs) located on the surface of T cells and thereby promote release of reactive oxygen species (ROS). The elevated ROS and inflammatory cytokines during sepsis condition have been reported to directly damage the endothelial cells, disrupt the barrier functions that might result in leakage of fluids, and inflammatory cells in tissues Moreover, several evidence have revealed that the calcium mediated activation of CaSR could produce systemic vasodilatory response by stimulating the nitric oxide production and opening of calcium-activated potassium channels, while infusion of its antagonist elevated the blood

Nonlinear relationship between ionized calcium and 28-day mortality in patients with sepsis: A retrospective cohort study from MIMIC-IV database

“…Calcium disorders are uncommon in the general population, except in special cases (e.g., renal failure), and are therefore often neglected [20,21] . Nevertheless, calcium derangements in sepsis are prevalent and should be taken seriously [22,23] . Total calcium levels are affected by a variety of factors, such as hypoalbuminemia or hypoalbuminemia, and may be less accurate (in the presence of renal disease, acid-base disturbances, or anionic perturbations), even after adjustment by algorithms [24][25][26] .…”

U-shaped Association between Serum Calcium Levels and 28-Day Mortality in Patients with Sepsis: A Retrospective Analysis of the MIMIC-III Database

“…Under sepsis condition, the proinflammatory cytokines IL-1β and IL-6 could upregulate the expression of calcium-sensing receptor in the parathyroid and kidney, ultimately reducing serum calcium levels ( 14 ). In turn, calcium derangements could also activate calcium-sensing receptors on T cell surfaces, promote the release of ROS and cytokine, damage endothelial cells and barrier function, and ultimately lead to fluid leakage, tissue inflammation and poor prognosis in sepsis ( 19 ). In addition, calcium influx could destroy the adhesion connections and cytoskeleton of endothelial cells, impairing endothelial cell integrity and exacerbating tissue damage and organ failure in septic patients ( 20 , 47 ).…”

“…Studies have indicated that the calcium derangements could activate calcium-sensing receptors located on T cell surfaces, thereby promoting the release of reactive oxygen species (ROS) and cytokine, ultimately leading to endothelial barrier damage, fluid leakage, myocardial cell apoptosis, and aggravating sepsis ( 19 ). Furthermore, inflammatory mediator-induced calcium influx could also lead to the disruption of adhesion connections and rearrangement of the cytoskeleton, thereby disrupting endothelial integrity, increasing permeability, and exacerbating the inflammatory response in sepsis ( 20 , 21 ).…”

Stimulation of the calcium‐sensing receptor induces relaxations of rat mesenteric arteries by endothelium‐dependent and ‐independent pathways via BKCa and KATP channels

“…In the vasculature, the CaSR is proposed to be functionally expressed in perivascular nerves, VSMCs, and VECs to regulate vasorelaxations (Awumey et al., 2008 , 2013 ; Bukoski et al., 1997 ; Greenberg et al., 2017 , 2019 ; Greenberg, Jahan, et al., 2016 ; Greenberg, Shi, et al., 2016 ; Ishioka & Bukoski, 1999 ; Loot et al., 2013 ; Mupanomunda et al., 1998 , 1999 ; Tang et al., 2016 ; Thakore & Ho, 2011 ; Wang & Bukoski, 1998 ; Weston et al., 2005 , 2008 ) vasoconstrictions (Li et al., 2011 ; Schepelmann et al., 2016 ; Wonneberger et al., 2000 ), and biphasic responses (Ohanian et al., 2005 ) involving diverse cellular mechanisms. As such, the CaSR may be a therapeutic target for cardiovascular conditions involving dysfunction of vascular tone such as hypertension and septic shock (Guo et al., 2018 ; Sood et al., 2022 ).…”