Candace Y W Lee1, Brenda K Huntley1, Daniel J McCormick1, Tomoko Ichiki1, S Jeson Sangaralingham1, Ondrej Lisy1, John C Burnett2. 1. Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine, Bioengineering & Physiology, and Biochemistry and Molecular Biology, College of Medicine Mayo Clinic, Guggenheim 915, 200 First Street S.W., Rochester, MN 55905, USA. 2. Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine, Bioengineering & Physiology, and Biochemistry and Molecular Biology, College of Medicine Mayo Clinic, Guggenheim 915, 200 First Street S.W., Rochester, MN 55905, USA burnett.john@mayo.edu.
Abstract
AIMS: Cenderitide is a novel dual natriuretic peptide (NP) receptor chimeric peptide activator, which targets the particulate guanylyl cyclase B (pGC-B) receptor and pGC-A unlike native NPs. Cenderitide was engineered to retain the anti-fibrotic properties of C-type natriuretic peptide (CNP)/pGC-B with renal-enhancing actions facilitated by fusion to the carboxyl terminus of Dendroaspis NP (DNP), a pGC-A agonist, to CNP. Here, we address significance of the DNP carboxyl terminus in dual pGC receptor activation and actions of cenderitide compared with CNP on renal function and cyclic guanosine monophosphate (cGMP) in vivo and ex vivo in normal canines. METHODS AND RESULTS: In vitro, only cenderitide and not CNP or three CNP-based variants was a potent dual pGC-A/pGC-B activator of cGMP production (from 5 to 237 pmol/mL) in human embryonic kidney (HEK) 293 cells overexpressing human pGC-A while in pGC-B overexpressing cells cenderitide increased cGMP production (from 4 to 321 pmol/mL) while the three CNP-based variants were weak agonists. Based upon our finding that the DNP carboxyl terminus is a key structural requirement for dual pGC-A/pGC-B activation, we defined in vivo the renal-enhancing actions of cenderitide compared with CNP. Cenderitide increased urinary cGMP excretion (from 989 to 5977 pmol/mL), net generation of renal cGMP (821-4124 pmol/min), natriuresis (12-242 μEq/min), and glomerular filtration rate (GFR) (37-51 mL/min) while CNP did not. We then demonstrated the transformation of CNP ex vivo into a renal cGMP-activating peptide which increased cGMP in freshly isolated glomeruli eight-fold greater than CNP. CONCLUSION: The current study establishes that dual pGC-A and pGC-B activation with CNP requires the specific carboxyl terminus of DNP. In normal canines in vivo and in glomeruli ex vivo, the carboxyl terminus of DNP transforms CNP into a natriuretic and GFR-enhancing peptide. Future studies of cenderitide are warranted in cardiorenal disease states to explore its efficacy in overall cardiorenal homeostasis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Cenderitide is a novel dual natriuretic peptide (NP) receptor chimeric peptide activator, which targets the particulate guanylyl cyclase B (pGC-B) receptor and pGC-A unlike native NPs. Cenderitide was engineered to retain the anti-fibrotic properties of C-type natriuretic peptide (CNP)/pGC-B with renal-enhancing actions facilitated by fusion to the carboxyl terminus of Dendroaspis NP (DNP), a pGC-A agonist, to CNP. Here, we address significance of the DNP carboxyl terminus in dual pGC receptor activation and actions of cenderitide compared with CNP on renal function and cyclic guanosine monophosphate (cGMP) in vivo and ex vivo in normal canines. METHODS AND RESULTS: In vitro, only cenderitide and not CNP or three CNP-based variants was a potent dual pGC-A/pGC-B activator of cGMP production (from 5 to 237 pmol/mL) in humanembryonic kidney (HEK) 293 cells overexpressing humanpGC-A while in pGC-B overexpressing cells cenderitide increased cGMP production (from 4 to 321 pmol/mL) while the three CNP-based variants were weak agonists. Based upon our finding that the DNP carboxyl terminus is a key structural requirement for dual pGC-A/pGC-B activation, we defined in vivo the renal-enhancing actions of cenderitide compared with CNP. Cenderitide increased urinary cGMP excretion (from 989 to 5977 pmol/mL), net generation of renal cGMP (821-4124 pmol/min), natriuresis (12-242 μEq/min), and glomerular filtration rate (GFR) (37-51 mL/min) while CNP did not. We then demonstrated the transformation of CNP ex vivo into a renal cGMP-activating peptide which increased cGMP in freshly isolated glomeruli eight-fold greater than CNP. CONCLUSION: The current study establishes that dual pGC-A and pGC-B activation with CNP requires the specific carboxyl terminus of DNP. In normal canines in vivo and in glomeruli ex vivo, the carboxyl terminus of DNP transforms CNP into a natriuretic and GFR-enhancing peptide. Future studies of cenderitide are warranted in cardiorenal disease states to explore its efficacy in overall cardiorenal homeostasis. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: S Jeson Sangaralingham; Brenda K Huntley; Fernando L Martin; Paul M McKie; Diego Bellavia; Tomoko Ichiki; Gerald E Harders; Horng H Chen; John C Burnett Journal: Hypertension Date: 2010-12-28 Impact factor: 10.190
Authors: C M O'Connor; R C Starling; A F Hernandez; P W Armstrong; K Dickstein; V Hasselblad; G M Heizer; M Komajda; B M Massie; J J V McMurray; M S Nieminen; C J Reist; J L Rouleau; K Swedberg; K F Adams; S D Anker; D Atar; A Battler; R Botero; N R Bohidar; J Butler; N Clausell; R Corbalán; M R Costanzo; U Dahlstrom; L I Deckelbaum; R Diaz; M E Dunlap; J A Ezekowitz; D Feldman; G M Felker; G C Fonarow; D Gennevois; S S Gottlieb; J A Hill; J E Hollander; J G Howlett; M P Hudson; R D Kociol; H Krum; A Laucevicius; W C Levy; G F Méndez; M Metra; S Mittal; B-H Oh; N L Pereira; P Ponikowski; W H W Tang; W H Wilson; S Tanomsup; J R Teerlink; F Triposkiadis; R W Troughton; A A Voors; D J Whellan; F Zannad; R M Califf Journal: N Engl J Med Date: 2011-07-07 Impact factor: 91.245
Authors: Tomoko Ichiki; John A Schirger; Brenda K Huntley; Frank V Brozovich; Joseph J Maleszewski; Sharon M Sandberg; S Jeson Sangaralingham; Soon J Park; John C Burnett Journal: J Mol Cell Cardiol Date: 2014-08-09 Impact factor: 5.000
Authors: K Doi; T Ikeda; H Itoh; K Ueyama; K Hosoda; Y Ogawa; J Yamashita; T H Chun; M Inoue; K Masatsugu; N Sawada; Y Fukunaga; T Saito; M Sone; K Yamahara; H Kook; M Komeda; M Ueda; K Nakao Journal: Arterioscler Thromb Vasc Biol Date: 2001-06 Impact factor: 8.311
Authors: Candace Y W Lee; Horng H Chen; Ondrej Lisy; Suzanne Swan; Courtney Cannon; Hsiao D Lieu; John C Burnett Journal: J Clin Pharmacol Date: 2009-04-24 Impact factor: 3.126
Authors: Yang Chen; Ye Zheng; Seethalakshmi R Iyer; Gerald E Harders; Shuchong Pan; Horng H Chen; Tomoko Ichiki; John C Burnett; S Jeson Sangaralingham Journal: J Mol Cell Cardiol Date: 2019-04-04 Impact factor: 5.000
Authors: Anja Glöde; Jennifer Naumann; Thorsten Gnad; Valentina Cannone; Ana Kilic; John C Burnett; Alexander Pfeifer Journal: Mol Metab Date: 2017-01-04 Impact factor: 7.422
Authors: Rika Kawakami; Candace Y W Lee; Christopher Scott; Kent R Bailey; John A Schirger; Horng H Chen; Sherry L Benike; Valentina Cannone; Fernando L Martin; S Jeson Sangaralingham; Tomoko Ichiki; John C Burnett Journal: Clin Pharmacol Ther Date: 2018-01-11 Impact factor: 6.875