Involvement of calpain in angiotensin II-induced aldosterone production in adrenal glomerulosa cells

Hdl Handle:
http://hdl.handle.net/10675.2/337504
Title:
Involvement of calpain in angiotensin II-induced aldosterone production in adrenal glomerulosa cells
Authors:
Seremwe, Mutsa P.
Abstract:
Aldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases such as hypertension, cardiofibrosis and congestive heart failure; therefore, a complete understanding of this process is important for developing more effective treatment strategies. Angiotensin II (AngII) regulates aldosterone production, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence of absence of penta-EF-hands. Caplains are involved in various cellular responses which include actin cytoskeletal remodeling and AngII/AT1R signaling. We hypothesized that calpain, in particular calpain 10, is activated by angiotensin II in adrenal glomerulosa cells and underlies increased aldosterone production. We conducted our experiments in two different adrenal glomerulosa cell models: primary bovine zona glomerulosa (zG) cells and human adrenocortical carcinoma cells (HAC15). Our results showed that the pain-calpain inhibitors, calpeptin and MDL 28170, inhibited AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII induced calpain activation in HAC15 cells. The typical (classical) calpain inhibitors PD-150606 and calpastatin peptide had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of a classical calpain in this process. Atypical calpains expressed by HAC15 cells include calpain 5, 7, 10, 15. The calpain-10 inhibitor, CYGAK inhibited both AngII-induced aldosterone production and CYP11B2 expression. Consistent with this result, knockdown of calpain 10 by an RNA interference technique inhibited aldosterone production and CYP11B2 expression. On the contrary overexpression of calpain-10 using adenoviral infection induced an increase in aldosterone production in the presence and absence of AngII. Our results indicate that AngII-induced activation of calpain 10 in adrenal glomerulosa cells underlies aldosterone production. Our results identify calpain-10 as a potential target for the development of drug therapies to inhibit aldosterone production for the treatment of hypertension.
Affiliation:
Department of Physiology
Issue Date:
Mar-2014
URI:
http://hdl.handle.net/10675.2/337504
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1527014979?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorSeremwe, Mutsa P.en
dc.date.accessioned2014-12-22T13:51:52Z-
dc.date.available2014-12-22T13:51:52Z-
dc.date.issued2014-03-
dc.identifier.urihttp://hdl.handle.net/10675.2/337504-
dc.description.abstractAldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases such as hypertension, cardiofibrosis and congestive heart failure; therefore, a complete understanding of this process is important for developing more effective treatment strategies. Angiotensin II (AngII) regulates aldosterone production, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence of absence of penta-EF-hands. Caplains are involved in various cellular responses which include actin cytoskeletal remodeling and AngII/AT1R signaling. We hypothesized that calpain, in particular calpain 10, is activated by angiotensin II in adrenal glomerulosa cells and underlies increased aldosterone production. We conducted our experiments in two different adrenal glomerulosa cell models: primary bovine zona glomerulosa (zG) cells and human adrenocortical carcinoma cells (HAC15). Our results showed that the pain-calpain inhibitors, calpeptin and MDL 28170, inhibited AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII-induced aldosterone production and CYP11B2 expression in these cells, in addition, AngII induced calpain activation in HAC15 cells. The typical (classical) calpain inhibitors PD-150606 and calpastatin peptide had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of a classical calpain in this process. Atypical calpains expressed by HAC15 cells include calpain 5, 7, 10, 15. The calpain-10 inhibitor, CYGAK inhibited both AngII-induced aldosterone production and CYP11B2 expression. Consistent with this result, knockdown of calpain 10 by an RNA interference technique inhibited aldosterone production and CYP11B2 expression. On the contrary overexpression of calpain-10 using adenoviral infection induced an increase in aldosterone production in the presence and absence of AngII. Our results indicate that AngII-induced activation of calpain 10 in adrenal glomerulosa cells underlies aldosterone production. Our results identify calpain-10 as a potential target for the development of drug therapies to inhibit aldosterone production for the treatment of hypertension.en
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1527014979?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectangiotensin IIen
dc.subjectCalciumen
dc.subjectadosteroneen
dc.subjectcalpainen
dc.titleInvolvement of calpain in angiotensin II-induced aldosterone production in adrenal glomerulosa cellsen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorBollag, Wendy B.en
dc.description.committeeIsales, Carlos; Seki, Tsugio; Cannon, Jennifer; Webb, Clintonen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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