Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate

Shuchong Pan, Horng Haur Chen, Cristina Correia, Haiming Dai, Tyra A. Witt, Laurel S. Kleppe, John C Jr. Burnett, Robert D. Simari

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Rationale: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. Objective: We utilized complementary in vitro and in vivo models to determine the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. Methods and Results: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addition of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochemistry. Conclusion: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors.

Original languageEnglish (US)
Article numbere112986
JournalPLoS One
Volume9
Issue number11
DOIs
StatePublished - Nov 24 2014

Fingerprint

protein disulfide-isomerase
guanosine monophosphate
Protein Disulfide-Isomerases
natriuretic peptides
Natriuretic Peptides
Cyclic GMP
surface proteins
Membrane Proteins
atrial natriuretic peptide
Atrial Natriuretic Factor
cells
C-Type Natriuretic Peptide
LLC-PK1 Cells
Brain Natriuretic Peptide
receptors
Guanylate Cyclase-Coupled Receptors
Immobilized Proteins
cell free system
surface plasmon resonance
guanylate cyclase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate. / Pan, Shuchong; Chen, Horng Haur; Correia, Cristina; Dai, Haiming; Witt, Tyra A.; Kleppe, Laurel S.; Burnett, John C Jr.; Simari, Robert D.

In: PLoS One, Vol. 9, No. 11, e112986, 24.11.2014.

Research output: Contribution to journalArticle

Pan, Shuchong ; Chen, Horng Haur ; Correia, Cristina ; Dai, Haiming ; Witt, Tyra A. ; Kleppe, Laurel S. ; Burnett, John C Jr. ; Simari, Robert D. / Cell surface protein disulfide isomerase regulates natriuretic peptide generation of cyclic guanosine monophosphate. In: PLoS One. 2014 ; Vol. 9, No. 11.
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abstract = "Rationale: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. Objective: We utilized complementary in vitro and in vivo models to determine the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. Methods and Results: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addition of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochemistry. Conclusion: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors.",
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AU - Pan, Shuchong

AU - Chen, Horng Haur

AU - Correia, Cristina

AU - Dai, Haiming

AU - Witt, Tyra A.

AU - Kleppe, Laurel S.

AU - Burnett, John C Jr.

AU - Simari, Robert D.

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