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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Ramseyer, Vanesa Daniela"],"institution":null,"degree_name":"Ph.D.","degree_level":"Open Access Dissertation","degree_discipline":"Physiology","degree_department":null,"school":null,"contributors":["Jeffrey L. Garvin"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-01-02T08:00:00Z","date_published":"2013-01-02T08:00:00Z","updated_at":"2026-07-24T05:59:33Z","subjects":["hypertension","kidney","nitric oxide","NKCC2","NOS3","thick ascending limb","Physiology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.wayne.edu/oa_dissertations/791","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Jeffrey L. Garvin"]},{"key":"dc:creator","label":"Author","values":["Ramseyer, Vanesa Daniela"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2013-01-01T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Physiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Open Access Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["hypertension","kidney","nitric oxide","NKCC2","NOS3","thick ascending limb","Physiology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.wayne.edu/oa_dissertations/791"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Thick Ascending Limb Nitric Oxide Production And Inhibition Of Nkcc2 Activity Are Impaired In Angiotensin Ii-Induced Hypertension"]}]}],"canonical_facts":{"dc:contributor":["Jeffrey L. Garvin"],"dc:creator":["Ramseyer, Vanesa Daniela"],"dc:date.available":["2013-01-01T08:00:00Z"],"dc:description.abstract":["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.
"],"dc:identifier":["https://digitalcommons.wayne.edu/oa_dissertations/791"],"dc:subject":["hypertension","kidney","nitric oxide","NKCC2","NOS3","thick ascending limb","Physiology"],"dc:title":["Thick Ascending Limb Nitric Oxide Production And Inhibition Of Nkcc2 Activity Are Impaired In Angiotensin Ii-Induced Hypertension"],"thesis:degree_discipline":["Physiology"],"thesis:degree_level":["Open Access Dissertation"],"thesis:degree_name":["Ph.D."]},"updated_at":"2026-07-24T05:59:33Z"}