Open Access Dissertation
Date of Award
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.
Ramseyer, Vanesa Daniela, "Thick Ascending Limb Nitric Oxide Production And Inhibition Of Nkcc2 Activity Are Impaired In Angiotensin Ii-Induced Hypertension" (2013). Wayne State University Dissertations. 791.