Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide

Shuchong Pan, Horng H. Chen, Deborah M. Dickey, Guido Boerrigter, Candace Lee, Laurel S. Kleppe, Jennifer L. Hall, Amir Lerman, Margaret M. Redfield, Lincoln R. Potter, John C. Burnett, Robert D. Simari

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics.Weidentified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intronretained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.

Original languageEnglish (US)
Pages (from-to)11282-11287
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
DOIs
StatePublished - Jul 7 2009

Fingerprint

Brain Natriuretic Peptide
Alternative Splicing
Kidney
Peptides
Glomerular Filtration Rate
Blood Vessels
Canidae
Heart Failure
Natriuresis
Mesangial Cells
Diuresis
Angiotensins
Renin
Immune Sera
Arterial Pressure
Amino Acids
Pharmaceutical Preparations

Keywords

  • Kidney
  • Myocardial
  • Vasoactive

Cite this

Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. / Pan, Shuchong; Chen, Horng H.; Dickey, Deborah M.; Boerrigter, Guido; Lee, Candace; Kleppe, Laurel S.; Hall, Jennifer L.; Lerman, Amir; Redfield, Margaret M.; Potter, Lincoln R.; Burnett, John C.; Simari, Robert D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 27, 07.07.2009, p. 11282-11287.

Research output: Contribution to journalArticle

Pan, Shuchong ; Chen, Horng H. ; Dickey, Deborah M. ; Boerrigter, Guido ; Lee, Candace ; Kleppe, Laurel S. ; Hall, Jennifer L. ; Lerman, Amir ; Redfield, Margaret M. ; Potter, Lincoln R. ; Burnett, John C. ; Simari, Robert D. / Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 27. pp. 11282-11287.
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AU - Boerrigter, Guido

AU - Lee, Candace

AU - Kleppe, Laurel S.

AU - Hall, Jennifer L.

AU - Lerman, Amir

AU - Redfield, Margaret M.

AU - Potter, Lincoln R.

AU - Burnett, John C.

AU - Simari, Robert D.

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N2 - Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics.Weidentified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intronretained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.

AB - Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics.Weidentified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intronretained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.

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