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Leptin, Melanocortin 4 receptor and Renal Nerves Play a Role in High Blood Pressure Programmed by Intrauterine Growth Restriction in Mouse
Author(s) -
Intapad Suttira
Publication year - 2016
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.30.1_supplement.1214.4
Subject(s) - offspring , medicine , endocrinology , leptin , blood pressure , intrauterine growth restriction , leptin receptor , denervation , kidney , pregnancy , gestation , biology , obesity , genetics
Intrauterine growth restriction (IUGR) is a risk factor for hypertension and cardiovascular disease in later life. However, the underlying mechanisms remain unclear. We previously showed that male mouse IUGR offspring exhibit high blood pressure and adiposity compared to control offspring. Increased circulating adipocyte‐derived leptin activates the brain melanocortin system, in particular the melanocortin 4 receptor (MC4R); these key factors increase renal sympathetic nerve activity and result in elevated blood pressure. Nonetheless, the effects of the leptin‐MC4R‐renal nerve pathway on blood pressure (BP) in IUGR is unknown. In the present studies, we tested the hypothesis that the leptin‐MC4R‐renal nerve pathway plays a role on the high BP observed in male IUGR mice. To determine the contribution of leptin and renal nerve activity to hypertension in male IUGR offspring, Pregnant C57BL/6J female mice underwent sham or reduced uterine perfusion (RUP) surgery at day 13 of gestation; pregnancy was allowed to come to full term. Offspring from RUP dams were IUGR; progeny from sham surgeries were used as controls. IUGR offspring had lower birth weights than controls ( P <0.01). Mean arterial pressure (MAP) was measured via carotid catheter in conscious adult (24 weeks old) male control and IUGR mice with or without bilateral renal denervation (RDV) for 2 weeks. IUGR offspring had a higher BP compared to controls (125.0±3.7 vs 112.1±2.1 mmHg; n=7, P <0.05). RDV did not alter MAP of control mice (110.7±1.8 mmHg; n=3) but significantly decreased MAP of IUGRs (115.0±2.0 mmHg; n=4). Serum leptin levels were significantly ( P <0.05) increased in IUGR (28.1±1.9 ng/ml; n=5) compared to controls (12.6±3.1 ng/ml; n=5). We also assessed the role of MC4R on BP of IUGR mice. Male and female MC4R +/− breeders were used to generate MC4R +/+ and MC4R −/− littermates to avoid the undesirable effects of obesity in MC4R −/− dams. RUP induction in pregnant MC4R +/− dams and MAP measurements of their offspring were conducted as aforementioned. IUGR MC4R +/+ mice had a significantly higher ( P <0.05) MAP (135.0±4.0 mmHg; n=4) than control MC4R +/+ animals (120.0±5.3 mmHg; n=4). MAP of control MC4R +/− (n=6) and MC4R −/− (n=3) were not significantly different from control MC4R +/+ . MAP of IUGR MC4R +/− (125.0±7.0 mmHg; n=5) was slightly lower but not significantly different from IUGR MC4R +/+ . However, IUGR MC4R −/− showed a significant decrease ( P <0.05) in MAP (117.0±6.7 mmHg; n=3) compared to IUGR MC4R +/+ . Together our data suggests that leptin, renal nerves, and MC4R are involved in IUGR programs an increase blood pressure in mice. Thus, the leptin‐MC4R‐renal nerve pathway is a putative mechanism underlying the hypertension of IUGR offspring. Support or Funding Information This work was supported by COBRE pilot grant GM104357 from National Institutes of Health