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Open Access Dissertation

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First Advisor

Jeffrey L. Garvin


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:

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;

2) the effect of angiotensin II on NOS3 expression was mediated by peroxynitrite;

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.

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.

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