Key result
Angiotensin II infusion for 5 days blunted NO production in response to endothelin-1 (-0.01 vs 0.17 AFU/min) by decreasing NOS3 expression by 40% and increasing T495 phosphorylation by 147%.
Why the study?
Does chronic ANG II infusion reduce NO production in the thick ascending limbs of rats?
Does chronic ANG II infusion reduce NO production in the thick ascending limbs of rats?
Absolute Event Rate: -0.01% vs 0.17%
p-value: p=<0.01
Chronic ANG II infusion impairs NO production in the thick ascending limbs by decreasing NOS3 expression and altering phosphorylation, which may contribute to the development of salt-sensitive hypertension.
Preclinical data link ANG II to impaired NO signaling in renal tubules; leaves open relevance to human hypertension therapy.
Thick ascending limbs reabsorb 30% of the filtered NaCl load. Nitric oxide (NO) produced by NO synthase 3 (NOS3) inhibits NaCl transport by this segment. In contrast, chronic angiotensin II (ANG II) infusion increases net thick ascending limb transport. NOS3 activity is regulated by changes in expression and phosphorylation at threonine 495 (T495) and serine 1177 (S1177), inhibitory and stimulatory sites, respectively. We hypothesized that NO production by thick ascending limbs is impaired by chronic ANG II infusion, due to reduced NOS3 expression, increased phosphorylation of T495, and decreased phosphorylation of S1177. Rats were infused with 200 ng·kg(-1)·min(-1) ANG II or vehicle for 1 and 5 days. ANG II infusion for 5 days decreased NOS3 expression by 40 ± 12% (P < 0.007; n = 6) and increased T495 phosphorylation by 147 ± 26% (P < 0.008; n = 6). One-day ANG II infusion had no significant effect. NO production in response to endothelin-1 was blunted in thick ascending limbs from ANG II-infused animals [ANG II -0.01 ± 0.06 arbitrary fluorescence units (AFU)/min vs. 0.17 ± 0.02 AFU/min in controls; P < 0.01]. This was not due to reduced endothelin-1 receptor expression. Phosphatidylinositol 3,4,5-triphosphate (PIP3)-induced NO production was also reduced in ANG II-infused rats (ANG II -0.07 ± 0.06 vs. 0.13 ± 0.04 AFU/min in controls; P < 0.03), and this correlated with an impaired ability of PIP3 to increase S1177 phosphorylation. We conclude that in ANG II-induced hypertension NO production by thick ascending limbs is impaired due to decreased NOS3 expression and altered phosphorylation.
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Ramseyer et al. (2014) studied Angiotensin II-induced hypertension. Angiotensin II vs. Vehicle (0.01 mol/l acetic acid) was evaluated on NO production in response to endothelin-1 (AFU/min) (p=<0.01). Angiotensin II infusion for 5 days blunted NO production in response to endothelin-1 (-0.01 vs 0.17 AFU/min) by decreasing NOS3 expression by 40% and increasing T495 phosphorylation by 147%.
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