Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses a-, b-, and g-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1b expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1b expression in the macula densa affects sodium excretion and saltsensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1b mRNA and protein were 30-and five-fold higher, respectively, than those of NOS1a in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1a-knockout (NOS1aKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P,0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

Hypertension during preeclampsia is associated with increased maternal vascular sensitivity to angiotensin II (ANGII). This study was designed to determine mechanisms whereby agonistic autoantibodies to the ANGII type I receptor (AT1-AA) enhance blood pressure (MAP) and renal vascular sensitivity to ANGII during pregnancy. First, we examined MAP and renal artery resistance index (RARI) in response to chronic administration of ANGII or AT1-AA or AT1-AA+ANGII in pregnant rats compared to control pregnant rats. In order to examine mechanisms of heightened sensitivity in response to AT1-AA during pregnancy we examined the role of endogenous ANGII in AT1-AA infused pregnant rats, Endothelin-1 and oxidative stress in AT1-AA+ANGII treated rats. Chronic ANGII increased MAP from 95 +/−2 in NP rats to 115 +/−2 mmHg. Chronic AT1-AA increased MAP to 118+/−1 mmHg in NP rats which further increased to 123+/−2 with AT1-AA+ANGII. Increasing ANGII from (10−11-10−8) decreased Af-Art diameter 15-20% but sharply decreased Af-Art diameter 60% in AT1-AA pretreated vessels. RARI increased from 0.67 in NP rats to 0.70 with AT1-AA infusion, which was exacerbated to 0.74 in AT1-AA + ANGII infused rats. AT1-AA-induced hypertension decreased with Enalapril but was not attenuated. Both tissue ET-1 and ROS increased with AT1-AA+ANGII compared to AT1-AA alone and blockade of either of these pathways had significant effects on MAP or RARI. These data support the hypothesis that AT1-AA, via activation of ET-1 and oxidative stress and interaction with endogenous ANGII, are important mechanisms whereby MAP and renal vascular responses are enhanced during preeclampsia.