Calcium sensing receptor as a novel target for treatment of sepsis induced cardio‐renal syndrome: Need for exploring mechanisms

Abstract

Calcium sensing receptor (CaSR) is localized in various organs and plays diverse physiological and pathological roles. Several scientific contributions have suggested the involvement of this cell surface receptor in cardiac and renal diseases. Sepsis is considered to be one of the major causes of ICU admissions. Cardiac dysfunction and acute kidney injury are major manifestations of sepsis and associated with reduced survival. Presently, the treatment approaches for management of sepsis induced cardiac depression and kidney injury are not satisfactory. Activation of CaSR has been demonstrated to induce cardiomyocyte damage upon lipopolysaccaharde (LPS) exposure by enhancing calcium ion levels, ROS (reactive oxygen species) production, promotion of inflammation and apoptosis. In addition, CaSR seems to be a critical regulator of intracellular calcium ion levels, which is directly implicated in induction of mitochondrial dysfunction and release of various pro‐apoptotic pathways during sepsis. Certain evidences have also documented the expression of CaSR on neutrophils and T lymphocytes, where it is involved in activation of neutrophils and induces apoptosis of immune cells. Moreover, the expression of CaSR has been confirmed in podocytes, mesangial cells, proximal tubular cells and its activation is responsible for podocyte effacement, mesangial cell proliferation and proximal tubular cell apoptosis. We have analyzed the existing evidences, and critically discussed the possible mechanisms underlying CaSR activation mediated cardiac and renal dysfunction in sepsis condition.

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

“…These discrepancies of the roles of CaSR on tumor progression in different cancers imply that it might be tissue or disease specific. Interestingly, CaSR is not only expressed on tumor cells, but also exists in T lymphocytes [ 47 , 48 ]. It was found that the activation of CaSR in T lymphocytes induces the secretion of cytokines and T-cell apoptosis [ 49 ].…”

The calcium-sensing receptor in inflammation: Recent updates

“…The CaSR has been hypothesized to provoke glomerular damage by coupling with the TRPC6 and boosting intracellular calcium influx, which has been ascribed as one of the principal culprits in the pathophysiology of membranous nephropathy (Huang et al, 2021) and in acute kidney injuries that frequently occur in septic patients (Yadav et al, 2021). However, as the authors suggested, direct evidences on these regards are missing and, thus, further studies are needed to clarify the possible implication of the CaSR in glomerular defects under inflammatory stimuli.…”

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

“…Intracellular calcium accumulation occurs in sepsis due to decreased uptake in sarcoplasmic reticulum and enhanced cytosolic calcium release by ryanodine receptor (Morse et al, 2017). During sepsis, cardiac dysfunction is evident due to elevated levels of calpain‐1, a calcium‐activated intracellular proteinase, which causes damage to the structural and contractile proteins dystrophin, myosin, and actin filaments of the cardiomyocytes (Celes et al, 2013; Yadav et al, 2021). The CaSR activation has been shown to elicit cardiomyocyte damage in response to lipopolysaccharide (LPS) exposure by increasing calcium release, inducing ROS production, inflammation, and apoptosis (Wang et al, 2013) A prior experimental study demonstrated the CaSR activation to be responsible for disrupting calcium balance, as observed in neonatal rat cardiomyocyte culture exposed to endotoxin LPS.…”

“…Intracellular calcium accumulation occurs in sepsis due to decreased uptake in sarcoplasmic reticulum and enhanced cytosolic calcium release by ryanodine receptor (Morse et al, 2017). During sepsis, cardiac dysfunction is evident due to elevated levels of calpain-1, a calciumactivated intracellular proteinase, which causes damage to the structural and contractile proteins dystrophin, myosin, and actin filaments of the cardiomyocytes (Celes et al, 2013;Yadav et al, 2021) et al, 2013). Presently, there is a lack of supporting evidence in-vivo for the effects of CaSR antagonists on the development of sepsis-induced cardiac depression and its implications for shock.…”