Jeson S. Sangaralingham

INTRARENAL RENIN ANGIOTENSIN SYSTEM ACTIVATION: PATHOPHYSIOLOGIC AND THERAPEUTIC IMPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE

Introduction: The Renin Angiotensin System (RAS) plays a pivotal role in mediating Cardiorenal Syndrome in acute decompensated heart failure (ADHF) and is one of the most targeted pathways in the treatment of HF. Human Angiotensinogen (AGT) is the precursor for all angiotensin (ANG) isoforms,

C-Type natriuretic peptide: a potential urinary biomarker for renal remodeling and fibrosis during aging

Background Renal aging is characterized by structural changes in the kidney, including fibrosis, which are often accompanied by reduced glomerular filtration rate (GFR) and elevated urinary protein excretion (UPE) that likely contributes to increased risk of kidney failure, cardiovascular disease and mortality in the elderly. Importantly a recent study, using biopsy in healthy kidney donors across six decades of life, demonstrated the presence of preclinical agerelated nephropathy which was otherwise undetectable using conventional clinical tests including GFR and UPE. Although, there are a number of biomarkers for renal disease and injury, there are few which target early renal remodeling prior to the onset of symptoms during natural aging. C-type natriuretic peptide (CNP) is highly expressed in renal cells, is potently anti-fibrotic, inhibits renal mesangial matrix accumulation and may play a role in podocyte-glomerular basement membrane (GBM) integrity. Since aging is associated with altered renal structure and function that may contribute to the development of kidney and heart failure, we sought to determine if CNP might serve as a urinary biomarker for global renal remodeling as a compensatory renal response to injury induced by aging.

Cenderitide, a novel dual GC-A and GC-B receptor activator, is a potent chronic cardiorenal fibroinhibiting peptide which suppresses aldosterone and reduces proteinuria in models of ardiorenal fibrosis

Background Cenderitide, also known as CD-NP, is a novel Mayo engineered designer natriuretic peptide (NP), which unlike native ANP, BNP and CNP co-activates both the guanylyl (GC)-A receptor to which ANP and BNP bind and GC-B to which CNP binds. Recognizing the aldosterone suppressing actions of GC-A activation and the potent inhibition of collagen synthesis and proliferation on fibroblasts to GC-B activation we hypothesized cenderitide would be a potent anti-fibrotic therapeutic agent. Here we defined the actions of chronic cenderitide administrated subcutaneously by pump in two models of cardiorenal fibrosis which included in a model of post myocardial infarction (MI) induced cardiorenal fibrosis and also in a model of chronic kidney disease produced by uninephrectomy (UNX).

Progressive decline in circulating CNP with aging is associated with progressive cardiac fibrosis and myocardial impairment

Background Cardiac aging is associated with altered myocardial structure and function that may contribute to the development of heart failure (HF), particularly in the elderly. C-type natriuretic peptide (CNP) is of endothelial cell origin and represents the most potent anti-fibrotic peptide of the natriuretic peptide (NP) family. CNP activates the NP receptor-B (NPR-B), which is found in high abundance in cardiac fibroblasts. Further, selective cardiac knockout of NPR-B contributes to exaggerated cardiomyocyte hypertrophy in response to pressure overload. In addition, infusion of CNP suppresses post-myocardial infarction (MI) induced cardiac fibrosis in a rodent model of MI. The impact of aging on circulating CNP and associated left ventricular (LV) structure and function are undefined.