Downregulation of P2y14 Receptor Expression Ameliorates Diabetic Cardiac Autonomic Neuropathy by Inhibiting Glial Ferroptosis Via the Nrf2/Gpx4 Axis

Abstract

Autonomic dysfunction in type 2 diabetes is a very common and serious complication, with diabetic cardiac autonomic neuropathy (DCAN) requiring particular attention because although it has an insidious onset, it may cause serious cardiac events and even sudden cardiac death. Purinergic signaling and ferroptosis play important roles in diabetes and its complications. However, whether purinergic receptor-mediated signaling pathways directly regulate cell death remains unclear. This study aimed to clarify the specific mechanisms by which P2Y14 receptor (P2Y14R) affects cardiac function through innervation. P2Y14R is highly expressed on satellite glial cells (SGCs) within the rat superior cervical ganglion (SCG). Silencing P2Y14R in the SCG ameliorates abnormal cervical sympathetic nerve discharge and cardiac function in DCAN rats, while its overexpression induces DCAN-like effects. Ferroptosis and inflammation were found to be involved in DCAN, and P2Y14R deletion mitigates these processes in the SCG. Mechanistically, the P2Y14R was activated by UDPG under high glucose conditions, and the function of its coupled Gi protein was activated to inhibit ERK phosphorylation, thereby inhibiting Nrf2 phosphorylation in the nucleus and the expression of its downstream target gene, GPX4. We also found that the downregulation of P2Y14R expression reduced the release of inflammatory factors by SGCs cultured in high glucose and Fer-1 treatment also produced consistent effects. Overall, we elucidated a possible mechanism by which the downregulation of P2Y14R expression in SGCs inhibits ferroptosis and inflammatory factor release through Nrf2, thereby alleviating abnormal stimulation of neurons and alleviating DCAN, providing a promising therapeutic target for the treatment of DCAN patients.

Keywords: Diabetic Cardiac Autonomic Neuropathy, P2Y14 receptor, ferroptosis, NRF2, GPX4