# Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $586,694

## Abstract

Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension
Project Summary
The major goal of our project is to determine how the central sympathetic nervous system is involved in
calcineurin inhibitor–induced hypertension (CIH). Calcineurin inhibitors, including cyclosporine and tacrolimus
(FK506), have revolutionized transplant medicine and substantially prolonged graft survival. However, persistent
hypertension remains a major adverse effect associated with long-term use of calcineurin inhibitors. Although
calcineurin inhibitors can increase the sympathetic nerve activity, the role of the central sympathetic nervous
system in the development of CIH has been largely overlooked. Also, previous work on the neural mechanisms
of CIH has focused on the acute effect of a single injection of calcineurin inhibitors. It remains unclear where and
how the augmented sympathetic outflow in CIH is generated in the brain. The hypothalamic paraventricular
nucleus (PVN) plays an important role in the pathogenesis of hypertension, and calcineurin is abundantly
expressed in the PVN. Recent studies indicate that α2δ-1 can directly regulate glutamate NMDA receptor
(NMDAR) activity in the central nervous system. Our preliminary studies showed that long-term treatment with
FK506 induced a gradual and sustained increase in arterial blood pressure, which persisted for many days even
after FK506 was discontinued. Furthermore, blocking NMDARs or inhibiting the α2δ-1–NMDAR complex in the
PVN profoundly reduced blood pressure and the sympathetic nerve discharges augmented by FK506 treatment.
On the basis of our strong preliminary data, we propose to test the overall hypothesis that prolonged treatment
with calcineurin inhibitors increases glutamatergic input to PVN presympathetic neurons by potentiating NMDAR
phosphorylation and α2δ-1–mediated synaptic NMDAR activity, leading to a sustained increase in sympathetic
outflow and hypertension. We will use several innovative in vitro and in vivo approaches to define the persistent
neural plasticity involved in CIH at molecular, cellular, and system levels. Our proposed studies are expected to
unravel the cellular and molecular substrates responsible for the sustained increase in sympathetic vasomotor
activity in CIH. This new information will greatly increase our understanding of the neural mechanisms of CIH
and enable the design of new strategies for treating this condition.

## Key facts

- **NIH application ID:** 10068033
- **Project number:** 1R01HL154512-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Hui-Lin Pan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,694
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068033

## Citation

> US National Institutes of Health, RePORTER application 10068033, Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension (1R01HL154512-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068033. Licensed CC0.

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