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Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients.

Abstract：

:Red blood cells (RBCs) enzymatically produce nitric oxide (NO) by a functional RBC-nitric oxide synthase (RBC-NOS). NO is a vascular key regulatory molecule. In RBCs its generation is complex and influenced by several factors, including insulin, acetylcholine, and calcium. NO availability is reduced in end-stage renal disease (ESRD) and associated with endothelial dysfunction. We previously demonstrated that, through increased phosphatidylserine membrane exposure, ESRD-RBCs augmented their adhesion to human cultured endothelium, in which NO bioavailability decreased. Since RBC-NOS-dependent NO production in ESRD is unknown, this study aimed to investigate RBC-NOS levels/activation, NO production/bioavailability in RBCs from healthy control subjects (C, N = 18) and ESRD patients (N = 27). Although RBC-NOS expression was lower in ESRD-RBCs, NO, cyclic guanosine monophosphate (cGMP), RBC-NOS Serine1177 phosphorylation level and eNOS/Calmodulin (CaM)/Heat Shock Protein-90 (HSP90) interaction levels were higher in ESRD-RBCs, indicating increased enzyme activation. Conversely, following RBCs stimulation with insulin or ionomycin, NO and cGMP levels were significantly lower in ESRD- than in C-RBCs, suggesting that uremia might reduce the RBC-NOS response to further stimuli. Additionally, the activity of multidrug-resistance-associated protein-4 (MRP4; cGMP-membrane transporter) was significantly lower in ESRD-RBCs, suggesting a possible compromised efflux of cGMP across the ESRD-RBCs membrane. This study for the first time showed highest basal RBC-NOS activation in ESRD-RBCs, possibly to reduce the negative impact of decreased NOS expression. It is further conceivable that high NO production only partially affects cell function of ESRD-RBCs maybe because in vivo they are unable to respond to physiologic stimuli, such as calcium and/or insulin.

journal_name

Mol Cell Biochem

journal_title

Molecular and cellular biochemistry

authors

Di Pietro N,Giardinelli A,Sirolli V,Riganti C,Di Tomo P,Gazzano E,Di Silvestre S,Panknin C,Cortese-Krott MM,Csonka C,Kelm M,Ferdinandy P,Bonomini M,Pandolfi A

doi

10.1007/s11010-016-2723-0

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

155-67

issue

1-2

eissn

0300-8177

issn

1573-4919

pii

10.1007/s11010-016-2723-0

journal_volume

417

pub_type

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Nitric oxide synthetic pathway and cGMP levels are altered in red blood cells from end-stage renal disease patients.