Thick Ascending Limb Nitric Oxide Production And Inhibition Of Nkcc2 Activity Are Impaired In Angiotensin Ii-Induced Hypertension

<p>Cardiovascular disease is the leading cause of death in the US. Hypertension, which affects about 30 % of the US population, is an important risk factor in the development of this disease. Inappropriately elevated sodium reabsorption by the kidney contributes to hypertension; therefore, studying the mechanisms that lead to enhanced sodium transport is important in understanding this pathology. The thick ascending limb (THAL) reabsorbs 30% of the filtered sodium chloride load. Nitric oxide (NO) produced by NO synthase type 3 (NOS3) increases cyclic GMP (cGMP) and inhibits THAL transport by reducing Na/K/2Cl cotransporter type 2 (NKCC2) activity. Interestingly, in angiotensin II-induced hypertension, THAL NaCl transport is enhanced. However, whether this is due to a direct effect of angiotensin II on the transporters or to a defect in the NO-signaling pathway is not known. We hypothesized that THAL NO production and inhibition of NKCC2 activity are impaired in angiotensin II-hypertension. We used THALs from normotensive and angiotensin II-infused hypertensive rats. We found that:</p> <p>1) in angiotensin II-induced hypertension, THAL NO production in response to physiological stimuli was decreased and this correlated with reduced NOS3 expression and phosphorylation at serine 1177;</p> <p>2) the effect of angiotensin II on NOS3 expression was mediated by peroxynitrite;</p> <p>3) NO-induced increases in cGMP and inhibition of NKCC2 activity were impaired in angiotensin II-hypertension and this was restored by inhibition of phosphodiesterase 5.</p> <p>In conclusion, we found that in angiotensin II-induced hypertension THAL NO production is reduced and NO-induced inhibition of NKCC2 activity is blunted due to increased phosphodiesterase 5 activity. We believe this could be one of the mechanisms by which angiotensin II increases NaCl transport by this nephron segment and that treatments that simultaneously increase NO production and inhibit phosphodiesterase 5 activity in the kidney could be useful in the management of hypertension.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Physiology

Year dc:date.available

2013

Author dc:creator

• Ramseyer, Vanesa Daniela

Contributors dc:contributor

• Jeffrey L. Garvin

• hypertension
• kidney
• nitric oxide
• NKCC2
• NOS3
• thick ascending limb
• Physiology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/791

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1790