B-type Natriuretic Peptide: Biology and Therapeutic Applications.

摘要

B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular and cardiorenal regulation. Studies have demonstrated a causal relationship between reduced production and/or impaired BNP release, and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remains poorly understood. Therefore, we generated and characterized a novel model of BNP deficiency, the Nppb-/- rat, in order to investigate the effects of BNP insufficiency on cardiac and renal structure, function, and survival.;The Nppb-/- male rat demonstrated a more accurate recapitulation of the clinical phenotype of BNP insufficiency; progressive and chronic adult onset hypertension, in addition to progressive nephropathy, cardiac hypertrophy, and decreased survival. Tangentially, Nppb-/- female rats developed early onset visceral arteritis, aneurysms, and intestinal necrosis in the absence of hypertension or an overt cardiorenal phenotype. Together, these results demonstrate two things; (1) the critical role of BNP in the development of systemic hypertension and associated end organ damage in adulthood, and (2) a possible sex-dependent role for BNP in maintaining cardiovascular homeostasis.;Further, the cardiorenal protective effects of BNP were tested in two models; first, an animal model of overt hypertensive heart disease, where BNP over expression prevented disease progression by lowering blood pressure, blunting cardiac fibrosis, and prolonging survival. Secondly; BNP therapy conferred a systemic reduction of systemic cyst burden in concert with depressed hepatorenal fibrosis processes in the PCK rat, a model of the chronic kidney disease, specifically, polycystic kidney disease (PKD).;An in vitro study of the mechanism behind BNPs renoprotective effects revealed a complex network of intracellular calcium modulation, and depressed proliferation markers unique to specific tissues, and cellular subtypes.;These studies provide new and novel insights into the biological consequences of BNP insufficiency and possible therapeutic applications of BNP supplementation in two diseases; chronic heart and chronic kidney disease.