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The role of Atrial Natriuretic Peptide in the development of renal and cardiac damage in a Dahl SS rat model
Author(s) -
Ilatovskaya Daria,
Winsor Kristen,
Levchenko Vladislav,
Prudnikov Oleh,
Blass Gregory,
Kriegel Alison,
Staruschenko Alexander
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.855.8
Subject(s) - medicine , endocrinology , atrial natriuretic peptide , blood pressure , kidney , natriuretic peptide , in vivo , excretion , biology , heart failure , microbiology and biotechnology
Atrial natriuretic peptide (ANP), encoded by the Nppa gene, is an osmoregulatory hormone that promotes salt excretion. A GWAS identified ANP as a causative factor of blood pressure development, and in humans ANP levels are suggested as an indicator of salt‐sensitivity. Recently, Flister et al. (Genome Res, 2013) generated a knockout of Nppa in the Dahl Salt‐Sensitive (SS) rat background (further referred to as the SS NPPA−/− rat). The aim of the current study was to provide mechanistic insights into the effects of ANP deficiency on renal and cardiac function in the Dahl SS rats. In this study hypertension was induced in SS NPPA−/− and control Dahl SS rats by placing them on a high salt diet (HS, 4% NaCl) for 21 days. A combination of in vivo techniques (blood pressure monitoring and GFR measurements) with ex vivo imaging, electrophysiological, and biochemical methods were used to test the role of ANP deficiency in the development of SS hypertension. Immunohistochemical analysis was employed to assess renal and cardiac damage. Chronic i.v. infusion of ANP in wild type SS rats (100 ng/kg/day) attenuated the salt‐induced increase in blood pressure in the wild type SS rats, whereas SS NPPA−/− rats demonstrated a significantly higher mean arterial pressure compared to SS controls when the rats were fed a HS diet: on day 21 of diet MAP was 185.8 ± 9 mmHg in SS NPPA−/− rats compared to 144.6 ± 4 mmHg in SS controls. Additionally, SS NPPA−/− rats showed exacerbated kidney damage as revealed by intensified kidney hypertrophy, higher glomerular injury scores, and increased renal arterial hypertrophy. GFR was found to be reduced in the control SS rats fed a HS diet compared to LS diet, however significance was not reached in the SS NPPA−/− group. SS NPPA−/− rats did exhibit reduced diuresis, as well as a trend for lower sodium and chloride excretion when fed a HS diet. The activity of Epithelial Sodium Channel (an important contributor to the development of SS hypertension) was found to be increased in the cortical collecting ducts of the SS NPPA−/− rats. Additionally, SS NPPA−/− rats fed a HS diet showed intensified cardiac damage compared to SS controls, as demonstrated by higher heart to body weight ratio, and a dramatically elevated interstitial fibrosis. However, ultrasound echocardiography revealed that although SS NPPA−/− rats have cardiac remodeling, they do not exhibit heart failure. Therefore, ANP is major regulator in the development of SS hypertension, and its deficiency leads to more severe cardiac and kidney damage. Further work will be devoted to discovering specific ANP‐associated molecular pathways that mediate its effects in SS hypertension, and assessing the therapeutic benefits of ANP for treating cardiovascular diseases. Support or Funding Information MCW RAC Pilot Grant (DVI) and NIH HL10880 (AS)