The Effect And Pathogenesis Of CaSR-TRPV2 Complex In Secondary Hyperparathyroidism

Background:Secondary hyperparathyroidism?SHPT?is a common serious complication of chronic kidney disease,with complicated pathogenesis and limited treatment options.Calcium-sensing receptor?CaSR?is the main regulator of intracellular calcium ion(Ca²⁺)concentration on the cell membrane,and regulates the synthesis and release of parathyroid hormone?PTH?.However,the mechanism of Ca²⁺influx caused by CaSR activation has not yet been fully elucidated.Objective:Finding the downstream calcium signal mediated by the combination of Ca²⁺and CaSR,fully understanding the pathogenesis of SHPT,and discovering new targets for prevention and treatment.Methods:?1?Transcriptome sequencing and western boltting were used to examine the expression level of CaSR and TRPV2 in parathyroid cells.?2?Co-Immunoprecipitation and immuno-colocalization were used to detect the location of CaSR and TRPV2 in human parathyroid cells.?3?Patch clamp was used to detect TRPV2 current in human parathyroid cells.?4?Calcium imaging was used to detect the effect of CaSR and/or TRPV2 on calcium signal in human parathyroid cells.?5?Elisa experiment was used to detect the effect of CaSR and/or TRPV2 on the release of PTH from human parathyroid cells.Results:?1?Transcriptome sequencing and western blotting showed that CaSR was lowly expressed while TRPV2 was highly expressed in SHPT patients.?2?CaSR interacts with TRPV2 to form a complex.?3?CaSR mediates Ca²⁺influx in human parathyroid cells through the TRPV2 channel.?4?CaSR agonist inhibits PTH release,TRPV2 si RNA/inhibitor promotes PTH release,TRPV2 agonist inhibits PTH release.Conclusions:CaSR-TRPV2 complex is a key pathway regulates the calcium signal of human parathyroid cells and the release of PTH.In SHPT,a large amount of PTH was released fromparathyroid cells,causing extracellular Ca²⁺concentration to increase,activating CaSR and further activating the highly expressed downstream TRPV2 Channels mediate Ca²⁺influx,forming negative feedback,and inhibiting PTH release.For TRPV2 is significantlyoverexpressed in SHPT patients,it may be another key target for SHPT treatment.