Aminoglycosides Induce Acute Cell Signaling and Chronic Cell Death in Renal Cells that Express the Calcium-Sensing Receptor

Abstract Context Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. Objectives The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. Methods Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. Results The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. Conclusion The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.

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Calcium-sensing receptor antagonism or lithium treatment ameliorates aminoglycoside-induced cell death in renal epithelial cells

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2008.01.003 ◽

2008 ◽

Vol 1782 (3) ◽

pp. 188-195 ◽

Cited By ~ 7

Author(s):

Claire E. Gibbons ◽

David Maldonado-Pérez ◽

Amish N. Shah ◽

Daniela Riccardi ◽

Donald T. Ward

Keyword(s):

Cell Death ◽

Epithelial Cells ◽

Lithium Treatment ◽

Calcium Sensing Receptor ◽

Receptor Antagonism ◽

Renal Epithelial Cells ◽

Calcium Sensing

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Pseudomonas syringae pv. actinidiae Effector HopAU1 Interacts with Calcium-Sensing Receptor to Activate Plant Immunity

International Journal of Molecular Sciences ◽

10.3390/ijms23010508 ◽

2022 ◽

Vol 23 (1) ◽

pp. 508

Author(s):

Jinlong Zhang ◽

Mingxia Zhou ◽

Wei Liu ◽

Jiajun Nie ◽

Lili Huang

Keyword(s):

Cell Death ◽

Pseudomonas Syringae ◽

Plant Pathogen ◽

Plant Immunity ◽

Resistance Breeding ◽

Plant Diseases ◽

Calcium Sensing Receptor ◽

Callose Deposition ◽

Calcium Sensing ◽

Plant Pathogen Interaction

Kiwifruit canker, caused by Pseudomonas syringae pv. actinidiae (Psa), is a destructive pathogen that globally threatens the kiwifruit industry. Understanding the molecular mechanism of plant-pathogen interaction can accelerate applying resistance breeding and controlling plant diseases. All known effectors secreted by pathogens play an important role in plant-pathogen interaction. However, the effectors in Psa and their function mechanism remain largely unclear. Here, we successfully identified a T3SS effector HopAU1 which had no virulence contribution to Psa, but could, however, induce cell death and activate a series of immune responses by agroinfiltration in Nicotiana benthamiana, including elevated transcripts of immune-related genes, accumulation of reactive oxygen species (ROS), and callose deposition. We found that HopAU1 interacted with a calcium sensing receptor in N. benthamiana (NbCaS) as well as its close homologue in kiwifruit (AcCaS). More importantly, silencing CaS by RNAi in N. benthamiana greatly attenuated HopAU1-triggered cell death, suggesting CaS is a crucial component for HopAU1 detection. Further researches showed that overexpression of NbCaS in N. benthamiana significantly enhanced plant resistance against Sclerotinia sclerotiorum and Phytophthora capsici, indicating that CaS serves as a promising resistance-related gene for disease resistance breeding. We concluded that HopAU1 is an immune elicitor that targets CaS to trigger plant immunity.

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