#2276 Serotonin receptor HTR2A drives parietal epithelial cell activation in glomerular disease downstream of platelet activation

Abstract Background and Aims The mechanisms driving the development of extracapillary lesions in crescentic glomerulonephritis (CGN) and focal segmental glomerulosclerosis (FSGS) remain poorly understood. This study investigates the role of serotonin (5-HT) and its receptors, specifically HTR2A and HTR2B, in murine models of these diseases. Method This study employed a combination of genetic, pharmacological, and in vitro approaches to elucidate the role of serotonin receptors in CGN and FSGS. Results We found that both receptors were upregulated in glomerular parietal epithelial cells in both human and murine CGN. We found that both genetic deletion and pharmacological inhibition of the 5-HT2A receptor effectively reduced glomerular crescents and sclerosis, while the compensatory upregulation of 5-HT2A receptors in response to 5-HT2B receptor deficiency or antagonism underscores a complex interplay between these receptor subtypes. Bone marrow-specific deletion and repletion of HTR2A-competent cells did not alter the course of experimental CGN, suggesting that the 2A signals driving CGN originate from the kidney. The Alport model, which is primarily degenerative, also benefitted in a similar way from 2A deletion, further corroborating the role of kidney resident 2A signaling in these diseases. Additionally, platelets were identified as a source of 5-HT and a crucial upstream factor in promoting PEC activation and exacerbating the disease, with their depletion leading to significant mitigation of disease severity. Finally, in vitro studies using murine PECs indicated the pivotal role of 5-HT signaling in PEC activation. Conclusion Our findings highlight a critical role of 5-HTR2A in PEC activation, proposing it as a new potential target for the treatment of glomerular kidney diseases.