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 language | English (US) |
|---|---|
| Pages (from-to) | 11282-11287 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 106 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 7 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide
AU - Pan, Shuchong
AU - Chen, Horng H.
AU - Dickey, Deborah M.
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.
PY - 2009/7/7
Y1 - 2009/7/7
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.
KW - Kidney
KW - Myocardial
KW - Vasoactive
UR - http://www.scopus.com/inward/record.url?scp=67650469513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650469513&partnerID=8YFLogxK
U2 - 10.1073/pnas.0811851106
DO - 10.1073/pnas.0811851106
M3 - Article
C2 - 19541613
AN - SCOPUS:67650469513
VL - 106
SP - 11282
EP - 11287
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 27
ER -