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The Cardiac Natriuretic Peptide System: Linking the Heart and Kidney in Cardiorenal Homeostasis and Therapeutics
Acknowledgments
Funding for this manuscript was provided by the NHLBI PO1 HL76611 and RO1 HL36634.
In 1981, the concept of the heart as an endocrine organ emerged with the discovery of the atrial natriuretic peptide (ANP) by de Bold in 1981. This initial report was followed later by the discovery of B-type natriuretic peptide (BNP) as an additional cardiac hormone which was structurally similar but genetically distinct. It is now established that the precursor prohormones proANP and proBNP are released from the heart in response to atrial stretch and other hemodynamic and inflammatory stimuli. These prohormones are processed to their biologically active forms ANP and BNP, principally by the protease corin, as well as to the biologically inactive NT-proANP and NT-proBNP forms with the kidney and the renin–angiotensin–aldosterone system (RAAS) a principle target. Thus, the cardiac natriuretic peptide (NP) system forms a cardiorenal axis in blood pressure and body fluid homeostasis. NEP, which is highly expressed in the kidney, is the principal enzyme which degrades the biologically active cardiac NPs (ANP and BNP). Importantly, NEP is not involved in the degradation of NT-proANP or NT-proBNP. Biologically active ANP and BNP bind to the same particulate guanylyl cyclase A receptor (pGC-A), activate the second messenger 3′,5′ cyclic guanosine monophosphate (cGMP) and result in pleiotropic actions including natriuresis, vasodilation, suppression of hypertrophy and fibrosis, inhibition of the renin–angiotensin–aldosterone system and metabolic protective properties.
Here we will review the biology of the NP/pGC-A/cGMP system in cardiorenal homeostasis with therapeutic implications as has recently been reviewed in detail. Special emphasis will be placed on the emerging therapeutic focus on NEP inhibition that has resulted in a novel small molecule therapeutic for heart failure and other cardiorenal syndromes and designer NPs that represent an innovative therapeutic approach to cardiorenal disease.
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Natriuretic Peptides
NPs represent a family of peptides that play a key role in preserving body fluid homeostasis by regulating intravascular volume, vascular tone, RAAS activation, and arterial pressure ( Fig. 9.1 ). Recently, a role for the cardiac peptides ANP and BNP in metabolic homeostasis has also been advanced. The NP system is highly preserved across species, and until now six NPs have been identified: A-type (ANP); B-type (BNP); C-type (CNP); D-type (DNP); ventricular NP (VNP), as well as the renal peptide Urodilatin (URO). NPs function as endogenous activators for a set of transmembrane NP receptors (NPR): CNP, evolutionarily the oldest of the NPs, binds to the particulate guanylyl cyclase B receptor (pGC-B, NPR-B), while all other NPs bind to the transmembrane pGC-A (NPR-A receptor). Particulate GC-A receptors are expressed in heart, kidney, brain, adrenals, adipocytes, and vasculature (both arteries and veins). Particulate GC-B receptors are expressed in kidney, brain, and veins, but less so in arteries.
NPR-C or the NP clearance receptor clears endogenous NPs from the circulation via hydrolysis (ranked from greatest to lowest degradation rate: VNP = ANP ≥ CNP > BNP = DNP). Clearance of NPs is also regulated via by the enzyme NEP which is discussed in greater detail later in this chapter. The differences in local NPR expression, degradation and clearance rates, and NP-binding affinity cause all six NPs to have unique and NP-specific properties. The binding of the NPs to their particulate guanylyl cyclase (pGC-A and pGC-B) receptors, induces a variety of autocrine, paracrine, and endocrine effects. Activated pGC receptors produce the second messenger cyclic GMP (cGMP) that in turn activates protein kinase G (PKG). Following this pGC/cGMP/PKG activation, biological responses occur which include inhibition of hypertrophy and fibrosis, vasodilatation and endothelial protection, natriuresis, aldosterone suppression, and lipolysis ( Fig. 9.2 ).
ANP and BNP are central in controlling body fluid and blood pressure homeostasis. ANP has renin-inhibiting properties, is a potent aldosterone inhibitor as well as an antagonist to the mineralocorticoid receptor (MR), and—via alternative processing of the ANP precursor, proANP—contributes to renal sodium and water handling via generation of urodilatin. BNP has been identified as an NP with natriuretic, RAAS-inhibitory, vasodilating, and lusitropic properties but less so than ANP. BNP also has robust diagnostic and prognostic properties as a biomarker for cardiorenal disease. DNP is a unique NP that has only been isolated from the venom gland of the green mamba and like ANP, BNP and URO activates pGC-A.
The report of a relative deficiency or low bioavailability of NPs in hypertension (HTN) provides a therapeutic opportunity for use of designer NPs, especially in special populations such as in resistant HTN where there remains a huge unmet therapeutic need. Further, altered molecular forms of ANP and BNP in heart failure (HF) with reduced biological action also provide rationale for NP therapeutics. Thus, development of new treatment regimes, with novel modes of action is a high priority, and from this perspective the concept of targeting (native) NPs for HF and HTN treatment strategies has attracted increased attention.
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