The objective of this application is to reduce the burden of cardiorenal fibrosis and dysfunction through the use of an innovative therapeutic peptide strategy via the activation of the particulate guanylyl cyclase B (GC-B) receptor. Another key component of this proposal is to clarify the important interaction between the heart and kidney and the fibrotic mechanisms that manifests in both organs due to cardiovascular disease (CVD) or chronic kidney disease (CKD). Increasing evidence has demonstrated that cardiorenal fibrosis is a hallmark of CVD and CKD and there is an evolving paradigm that disease in one organ, either the heart or kidney, induces fibrosis and functional impairment of the other organ. Yet, the pathophysiological mechanism that elicits this fibrotic phenotype simultaneously in both organs is not understood and if left untreated, manifests clinically as cardiorenal syndrome. Thus a real urgency exists to develop effective anti-fibrotic therapeutic strategies to reduce the risk of both heart and kidney failure. Accordingly, studies have supported that the GC-B/cGMP pathway, activated by endothelial and renal-derived C-type natriuretic peptide (CNP), functions as a key regulator of fibrosis by inhibiting fibroblast proliferation and collagen synthesis, suppressing pro-fibrotic factors and preserving endothelial/vascular integrity. Additionally, we have recently reported that urinary CNP is elevated with fibrotic disease or injury, thus suggesting the potential for urinary CNP to serve as a novel, non- invasive fibrosis biomarker. Here we advance our novel first-in-class GC-B activator, C53, as an innovative therapeutic peptide strategy for cardiorenal fibrosis. Our preliminary studies demonstrate that C53 possesses potent cGMP-generating actions via selective GC-B receptor activation and has a longer circulating half-live, than biologically active CNP. Thus, C53 may represent an advanced drug design strategy that overcomes the limitation of native CNP's low bioavailability. Our central hypothesis is that chronic administration of the novel GC-B peptide activator, C53, can interrupt the cascade of cellular fibro-stimulatory responses in the heart and kidney that culminate in cardiorenal fibrosis and dysfunction triggered by disease in the heart (CVD) or kidney (CKD). This proposal will also define urinary CNP as a non-invasive biomarker for cardiorenal fibrotic remodeling in human myocardial and renal disease. The impact of our translational application is high, addressing the need for new drugs and biomarkers for cardiorenal fibrosis of which there are no effective strategies to treat or detect this disease phenotype.
Our Specific Aims are as follows:
Aim 1 : To establish the cellular mechanisms by which C53 exerts its anti-fibrotic actions on human cardiac and renal fibroblasts in vitro.
Aim 2 : To establish in vivo, that chronic subcutaneous infusion of C53 will prevent adverse cardiorenal fibrosis and dysfunction in a rat model of cardiac or renal fibrotic disease.
Aim 3 : To prospectively define circulating and urinary levels of CNP in humans with myocardial and/or renal disease and healthy adult volunteers.

Public Health Relevance

There is a huge unmet need for novel effective drugs and biomarkers for cardiorenal fibrosis of which there are no effective strategies to treat or detect this phenotype seen in heart and kidney disease. This proposal seeks to develop a novel first-in-class GC-B activator as an innovative therapeutic peptide strategy for cardiorenal fibrosis. We also propose to advance a novel urinary biomarker strategy to detect cardiorenal fibrotic remodeling in humans with heart and kidney disease. These studies will improve our understanding of cardiorenal fibrosis and eventually lead to novel ways to treat and diagnosis fibrosis in heart and kidney disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Adhikari, Bishow B
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Mayo Clinic, Rochester
United States
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Sangaralingham, Lindsey R; Sangaralingham, S Jeson; Shah, Nilay D et al. (2018) Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure. Circ Heart Fail 11:e004302
Sangaralingham, S Jeson; Burnett Jr, John C (2018) Relaxing With C-Type Natriuretic Peptide, the Guanylyl Cyclase B Receptor, and Pericytes. Circulation 138:509-512