Abstract 144: Macula Densa NOS1β-Mediated TGF Response Plays an Important Role in the Sex Differences in Salt-Sensitive Hypertension

Abstract

Females are resistant to salt-sensitive hypertension than males, but the mechanisms are not completely elucidated. We recently demonstrated that a decisive role of macula densa neuronal nitric oxide synthase β (NOS1β) in the tubuloglomerular feedback (TGF) response, long-term control of glomerular filtration rate (GFR), sodium excretion and blood pressure. Thus, in this study, we tested a hypothesis that high salt diet-induced upregulation of NOS1β in the macula densa is exaggerated in females than males, which induces more inhibition in TGF response, thereby facilitating sodium excretion and contributing to the resistance to salt-sensitive hypertension. We used microperfusion, micropuncture, clearance of FITC–insulin and radio telemetry to examine the sex differences in macula densa NOS1β expression, nitric oxide (NO) generation, TGF response, kidney clearance function and mean arterial pressure (MAP) in response to a high salt diet in C57BL/6 and macula densa–specific NOS1 knockout (KO) mice. In C57BL/6 mice, males and females had comparable basal levels in macula densa NOS1β expression, NO generation, TGF response and MAP. An 2-week high salt diet resulted in more increases of NOS1β expression in female mice than male mice (3.4±0.3-fold vs. 1.7±0.1-fold), greater increases of NO generation by the macula densa in female mice than male mice (99.1±19.8 % vs. 55.6±11.6 %), and more attenuation in TGF responses in vivo (48.7±7.2 % vs. 25.5±2.9 %) as well as TGF response in vitro (58.5±5.6 % vs. 33.7±9.3 % )in female mice than male mice. Additionally, in response to a 2-week high salt diet along with low dose Ang II, the MAP increased by 13.7±4.2 mmHg in females and 35.4±5.6 mmHg in males with a sex difference of 21.7±4.7 mmHg. In the KO mice, the high salt diet had no significant effects on the macula densa NOS1β expression, NO generation, TGF response in vivo or in vitro in both females and males. Moreover, in response to the high salt diet along with low dose Ang II, the MAP increased by 41.7±4.1 mmHg in KO females and 52.6±3.8 mmHg in KO males with a sex difference of 10.9±3.1 mmHg, which was significantly reduced compared with C57BL/6 mice. In conclusion, macula densa NOS1β-mediated TGF response plays an important role in the sex difference in salt-sensitive hypertension.