# Adenosine in Renal Sympathetic Neurotransmission

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $352,125

## Abstract

During the previous funding period we discovered that endogenous adenosine by activating A1
receptors is a major determinant of the renovascular response to renal sympathetic nerve stimulation (RSNS).
This conclusion is based on our observations that selective A1-receptor antagonism in rats and A1-receptor
deletion in mice suppresses renovascular responses to RSNS. Moreover, we discovered that there are three
reasons A1 receptors importantly contribute to RSNS-induced renal vasoconstriction: 1) RSNS triggers
adenosine formation; 2) Preglomerular microvessels express high levels of vasoconstrictor A1 receptors; and
3) In the renal vasculature, the Gi signaling pathway (which A1 receptors engage) converges with the Gq
signaling pathway (which α1-adrenoceptors engage) to trigger “coincident signaling” at phospholipase C
leading to augmentation by adenosine of the vasoconstrictor response to released norepinephrine (NE).
Because ATP is released from noradrenergic varicosities, as well as from vascular smooth muscle and
endothelial cells, the main precursor of adenosine in the sympathetic neuroeffector junction is likely ATP.
CD39 catalyzes the metabolism of ATP to ADP and ADP to AMP, and CD73 metabolizes AMP to adenosine;
thus these twin ecto-enzymes acting in tandem are considered the most important mechanism for producing
extracellular adenosine from ATP. Surprisingly, however, our experiments show that neither pharmacological
inhibition of CD39 nor genetic deletion of CD73 attenuates renovascular responses to RSNS. Instead, our
preliminary findings suggest that inhibition of kidney non-specific alkaline phosphatase (KAP) markedly
attenuates both renovascular responses to RSNS and adenosine release by RSNS. We hypothesize that
renovascular KAP, rather than CD39/CD73, is necessary for the formation of the pool of adenosine that
participates in RSNS-induced renal vasoconstriction. If our hypothesis is correct then KAP inhibition,
knockdown (KAP-/+) or knockout (KAP-/-) should attenuate RSNS- and NE-induced renovascular responses
and purine release. Moreover, our hypothesis predicts that A1-receptor stimulation should rescue (reverse) the
suppression of renovascular responses to NE induced by KAP inhibition or knockdown/knockout. These
predictions will be tested in Aims #1 and #2, respectively. We have strong preliminary evidence that coincident
signaling between A1 receptors and NE not only enhances renal vasoconstriction but also induces the
renovascular release of soluble KAP – which could further enhance adenosine formation and potentiate
renovascular responses to NE. Aim #3 of this proposal will determine whether and how A1-receptor stimulation
augments RSNS- or NE-induced release of soluble KAP. Using the world’s first A1-receptor knockout Dahl salt
sensitive rat, our final aim (Aim #4) will “put our hypothesis to work” by determining whether A1-receptor
knockout and long-term KAP inhibition attenuate in vivo RSNS-induced renal vasoconstriction ...

## Key facts

- **NIH application ID:** 9972749
- **Project number:** 5R01DK091190-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** EDWIN Kerry JACKSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,125
- **Award type:** 5
- **Project period:** 2016-09-22 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972749

## Citation

> US National Institutes of Health, RePORTER application 9972749, Adenosine in Renal Sympathetic Neurotransmission (5R01DK091190-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9972749. Licensed CC0.

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