Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene.

Abstract

Brain natriuretic peptide (BNP) is a cardiac hormone that occurs predominantly in the ventricle. To study the roles of BNP in chronic cardiovascular regulation, we isolated mouse BNP cDNA and genomic clones, and generated transgenic mice with elevated plasma BNP concentration. The mouse BNP gene was organized into three exons and two introns. Two BNP mRNA species were identified, which were generated by the alternative mRNA splicing. The ventricle was a major site of BNP production in mice. Mouse preproBNP was a 121-(or 120-) residue peptide, and its COOH-terminal 45-residue peptide was the major storage form in the heart. Transgenic mice carrying the human serum amyloid P component/mouse BNP fusion gene were generated so that the hormone expression is targeted to the liver. In the liver of these mice, considerable levels of BNP mRNA and peptide were detected, reaching up to 10-fold greater than in the ventricle. These animals showed 10-to 100-fold increase in plasma BNP concentration accompanied by elevated plasma cyclic GMP concentration, and had significantly lower blood pressure than their nontransgenic littermates. The present study demonstrates that these mice provide a useful model system with which to assess the roles of BNP in cardiovascular regulation and suggests the potential usefulness of BNP as a long-term therapeutic agent. (J. Clin. In west. 1994.

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

“…Generation of BNP-Tg mice (line 55) harbouring 20 copies of the transgene under the control of the human serum amyloid P component promoter has been reported elsewhere [22][23][24]. This promoter is active only in the liver after birth [22].…”

“…Administration of ANP exerted beneficial effects in experimental and clinical acute renal failure [20,21]. We generated hypotensive transgenic mice overexpressing the mouse gene encoding BNP (Nppb) in the liver (BNP-Tg mice), which showed more than a 100-fold increase in plasma BNP and constitutive elevation of urinary guanosine 3′,5′-cyclic monophosphate (cGMP) levels [22]. Using this animal model, we successfully demonstrated amelioration of renal injury after renal ablation [23] and in proliferative glomerulonephritis [24].…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…Gene deletion of murine GC-A, GC-C, ANP, BNP, and CNP along with transgenic over-expression of ANP and BNP have pointed to some of the fundamental roles of these receptors and ligands in murine physiology [168][169][170][171][172][173][174][175][176].…”

“…Transgenic mice over-expressing BNP were generated using a fusion construct between the human serum amyloid P component promoter and murine BNP gene; BNP is overproduced in the liver and circulating BNP concentration is increased [176]. BNP transgenic mice have blood pressure decreases of 2O'-3O mmHg and a 30% reduction in heart-tobody weight ratio [176,188], and surprisingly, exhibit skeletal overgrowth due to high-turnover endochondral ossification [189].…”

Augmented expression of obese (ob) gene during the process of obesity in genetically obese‐hyperglycemic Wistar fatty (falfa) rats

“…Northern blot analysis was performed [12] using the 32P-labeled rat ob [3] and human LPL [8,13] cDNA fragments as probes.…”