Brain α2δ-1–Bound NMDA Receptors Drive Calcineurin Inhibitor–Induced Hypertension
Jing-Jing Zhou, Jian-Ying Shao, Shao-Rui Chen, Hui-Lin Pan- Cardiology and Cardiovascular Medicine
- Physiology
BACKGROUND:
Calcineurin is highly enriched in immune T cells and in the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. Here, we determined whether α2δ-1 plays a role in calcineurin inhibitor–induced synaptic NMDAR hyperactivity in the PVN and hypertension development.
Methods and Results:
Immunoblotting and coimmunoprecipitation assays revealed that prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1 (the obligatory NMDAR subunit), and the α2δ-1–GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1–NMDAR interaction with an α2δ-1 C-terminus peptide. Whole-cell recordings in brain slices showed that treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, telemetry recording showed that concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice.
Conclusions:
These findings indicate that α2δ-1 is essential for calcineurin inhibitor–induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1–bound NMDARs represent new targets for treating calcineurin inhibitor–induced hypertension.