Evenepoel, Pieter

Gross, Peter

Meijers, Björn KI

Meye, Constanze

Stasch, Johannes-Peter

BMC Pharmacology

English

PubMed

Björn KI Meijers

Constanze Meye

Johannes-Peter Stasch

Peter Gross

Pieter Evenepoel

Springer - Publisher Connector

BioMed CentralBMC Pharmacology
ssOpen AccePoster presentation
The uremic retention solute p-cresyl sulfate alters NO signal 
transduction by alteration of the soluble guanylate cyclase redox 
state
Björn KI Meijers*1, Constanze Meye2, Johannes-Peter Stasch3, Peter Gross2 
and Pieter Evenepoel1
Address: 1Internal Medicine, Department of Nephrology, University Hospitals Leuven, Leuven, Belgium, 2Division of Nephrology, Department of 
Internal Medicine III, Technical University Dresden, Dresden, Germany and 3Bayer Schering Pharma, Cardiovascular Research, Wuppertal, 
Germany
Email: Björn KI Meijers* - bjorn.meijers@uz.kuleuven.ac.be
* Corresponding author    
Introduction
Chronic kidney disease (CKD) is associated with excessive
cardiovascular disease and mortality. Nitric oxide (NO) –
soluble guanylate cyclase (sGC) signaling is impaired in
CKD patients, contributing to a near ubiquitous endothe-
lial dysfunction. Loss of kidney function induces major
alterations in the blood concentration of numerous mol-
ecules. Several of these so-called uremic retention solutes
are known to interfere with NO-sGC signaling. p-Cresol/
p-cresyl sulfate (PCS), a prototypic representative of the
protein-bound uremic retention solutes, is independently
associated with overall mortality and incident cardiovas-
cular disease in hemodialysis patients. The mechanisms
underlying this association remain elusive. We hypothe-
sized that PCS interferes with NO-sGC signaling, thereby
contributing to CKD-associated endothelial dysfunction
and cardiovascular mortality.
Materials and methods
We investigated the effects of PCS on NO and cGMP gen-
eration and on eNOS, sGC and caveolin-1 expression by
human umbilical vein endothelial cells (HUVEC). The
effects of PCS on sGC activity were studied using purified
rat sGC and sGC overexpressing CHO cells. Rabbit saphe-
nous arteries were used for functional studies on the effect
of PCS on vascular relaxation. The reduced (NO sensitive)
sGC was activated by the sGC stimulator BAY 41-2272.
Activity of the oxidized (NO-insensitive) sGC was probed
using the sGC activator BAY 58-2667. p-Cresyl sulfate was
synthesized according to Feigenbaum. Purity was > 99%.
Results
PCS reduced the calcium-ionophore stimulated cGMP
generation by HUVEC in a time and dose-dependent fash-
ion. While we observed a small significant reduction in
eNOS expression (-15%, P = 0.01), NOx concentrations
were not changed. Moreover, PCS reduced the NO-donor
NOC-9 stimulated cGMP generation. As PCS did not
affect sGC expression, we speculated that PCS changed the
sGC redox state, thereby affecting sGC activity. BAY 58-
2667 stimulated cGMP generation was increased in the
presence of PCS, both at purified rat sGC and in sGC over-
expressing CHO cells. In a model of phenylephedrine pre-
contracted rabbit saphenous arteries, presence of PCS
increased vasodilator activity of BAY 58-2667, while
reducing the effects of sodium nitroprusside.
Conclusion
The uremic retention solute p-cresyl sulfate reduces NO-
sGC signaling, through a shift of the sGC redox status
towards the NO-insensitive oxidized/heme-free state. We
believe PCS is the first known endogenous molecule to
from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications
Regensburg, Germany. 19–21 June 2009
Published: 11 August 2009
BMC Pharmacology 2009, 9(Suppl 1):P47 doi:10.1186/1471-2210-9-S1-P47
<supplement> <title> <p>4th International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S1-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S1-info.pdf</url> </supplement>
This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S1/P47
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change the sGC redox equilibrium. As altered sGC redox
status contributes to impaired NO-sGC-cGMP signaling
in patients with chronic kidney disease, this pathway may
prove a novel therapeutic target in patients with chronic
kidney disease and beyond.Page 2 of 2
(page number not for citation purposes)


The uremic retention solute p-cresyl sulfate alters NO signal transduction by alteration of the soluble guanylate cyclase redox state

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The uremic retention solute p-cresyl sulfate alters NO signal transduction by alteration of the soluble guanylate cyclase redox state

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