Novel Renal Targeted Protein Therapeutics in Experimental Overt Heart Failure and Renal Dysfunction with an Innovative Chimeric Natriuretic Peptide: ABC-NP

Abstract

Background: C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced in the endothelium and is a ligand for the NPR-B receptor. CNP has a potent cardiac unloading action and reduces blood pressure but has minimal renal actions. Studies have revealed that in overt heart failure (HF), the predominant natriuretic peptide (NP) receptor in the kidney is the NPR-B receptor. Based on our previous knowledge, we mutated the amino acid (AA) sequence in the ring structure of CNP replacing three AAs GSM with REA and fused a novel 5 AA sequence from ANP (RMDRI) to the N-terminus and a 6 AA sequence (KVLRRH) from BNP to the C-terminus of CNP. We hypothesized that this novel hybrid peptide ABC-NP would maintain CNP's inherent cardiac unloading characteristics and gain renal enhancing properties without hypotensive effects. Methods: We determined the cardiorenal and humoral actions of intravenous infusion of ABC-NP at 2 pmol/Kg/min, 10 pmol/Kg/min and 100 pmol/Kg /min in 7 dogs with rapid ventricular pacing induced overt HF with renal dysfunction (240 bpm for 10 days). * p<0.05 Results: Infusion of ABC-NP enhanced glomerular filtration rate (GFR), from 31±5 to 45±7, 51±6 and 60±7 ml/min*, induce natriuresis (from 3±2 to 12±8, 17±13 and 29±19 μEq/min*) and diuresis (from 0.13±0.03 to 0.4±0.1, 0.6±0.2 and 0.8±0.3 ml/min*) with a modest reduction in pulmonary capillary wedge pressure (PCWP) (from 21±1 to 19±1, 20±1 and 21±1 mmHg*). Importantly, mean arterial blood pressure was maintained. Suppression of plasma renin* and increases in urinary cGMP* and cAMP* excretion were observed. Conclusion: This novel peptide ABC-NP has potent natriuretic and GFR enhancing actions without hypotensive properties in an experimental model of overt CHF together with suppression of renin. These studies also suggest that the three AA sequence GSM in the CNP ring may be the mediator of the vasoactive properties of CNP. Further key sequences from ANP added to the N-terminus of CNP and of BNP in the C-terminus of CNP may be responsible for the renal actions of this new peptide. The increase of urinary cAMP excretion in addition to cGMP excretion suggests that this novel peptide may have biological effects beyond the known natriuretic peptide receptors. This renal specific peptide may have potential therapeutic benefit in states of renal dysfunction to enhance GFR without the detrimental side effect of hypotension. Background: C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced in the endothelium and is a ligand for the NPR-B receptor. CNP has a potent cardiac unloading action and reduces blood pressure but has minimal renal actions. Studies have revealed that in overt heart failure (HF), the predominant natriuretic peptide (NP) receptor in the kidney is the NPR-B receptor. Based on our previous knowledge, we mutated the amino acid (AA) sequence in the ring structure of CNP replacing three AAs GSM with REA and fused a novel 5 AA sequence from ANP (RMDRI) to the N-terminus and a 6 AA sequence (KVLRRH) from BNP to the C-terminus of CNP. We hypothesized that this novel hybrid peptide ABC-NP would maintain CNP's inherent cardiac unloading characteristics and gain renal enhancing properties without hypotensive effects. Methods: We determined the cardiorenal and humoral actions of intravenous infusion of ABC-NP at 2 pmol/Kg/min, 10 pmol/Kg/min and 100 pmol/Kg /min in 7 dogs with rapid ventricular pacing induced overt HF with renal dysfunction (240 bpm for 10 days). * p<0.05 Results: Infusion of ABC-NP enhanced glomerular filtration rate (GFR), from 31±5 to 45±7, 51±6 and 60±7 ml/min*, induce natriuresis (from 3±2 to 12±8, 17±13 and 29±19 μEq/min*) and diuresis (from 0.13±0.03 to 0.4±0.1, 0.6±0.2 and 0.8±0.3 ml/min*) with a modest reduction in pulmonary capillary wedge pressure (PCWP) (from 21±1 to 19±1, 20±1 and 21±1 mmHg*). Importantly, mean arterial blood pressure was maintained. Suppression of plasma renin* and increases in urinary cGMP* and cAMP* excretion were observed. Conclusion: This novel peptide ABC-NP has potent natriuretic and GFR enhancing actions without hypotensive properties in an experimental model of overt CHF together with suppression of renin. These studies also suggest that the three AA sequence GSM in the CNP ring may be the mediator of the vasoactive properties of CNP. Further key sequences from ANP added to the N-terminus of CNP and of BNP in the C-terminus of CNP may be responsible for the renal actions of this new peptide. The increase of urinary cAMP excretion in addition to cGMP excretion suggests that this novel peptide may have biological effects beyond the known natriuretic peptide receptors. This renal specific peptide may have potential therapeutic benefit in states of renal dysfunction to enhance GFR without the detrimental side effect of hypotension.