Calpain-10 Activity Underlies Angiotensin II-Induced Aldosterone Production in an Adrenal Glomerulosa Cell Model

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 including hypertension and congestive heart failure; therefore, a complete understanding of aldosterone production is important for developing more effective treatments. Angiotensin II (AngII) regulates steroidogenesis, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence or absence of penta-EF-hands, which are involved in various cellular responses. We hypothesized that calpain, in particular calpain-10, is activated by AngII in adrenal glomerulosa cells and underlies aldosterone production. Our studies showed that pan-calpain inhibitors reduced AngII-induced aldosterone production in 2 adrenal glomerulosa cell models, primary bovine zona glomerulosa and human adrenocortical carcinoma (HAC15) cells, as well as CYP11B2 expression in the HAC15 cells. Although AngII induced calpain activation in these cells, typical calpain inhibitors had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of classical calpains in this process. However, an inhibitor of the atypical calpain, calpain-10, decreased AngII-induced aldosterone production. Consistent with this result, small interfering RNA (siRNA)-mediated knockdown of calpain-10 inhibited aldosterone production and CYP11B2 expression, whereas adenovirus-mediated overexpression of calpain-10 resulted in increased AngII-induced aldosterone production. Our results indicate that AngII-induced activation of calpain-10 in glomerulosa cells underlies aldosterone production and identify calpain-10 or its downstream pathways as potential targets for the development of drug therapies for the treatment of hypertension.

<p>Calpain-10 drives podocyte apoptosis and renal injury in diabetic nephropathy</p>

“…Calpain 10, a member of the calpain family, is a ubiquitously expressed mitochondrial and cytosolic Ca2+-regulated cysteine protease, researches have demonstrated that overexpression of Calpain 10 leads to mitochondrial dysfunction and cell death 29. Other research showed that Angiotensin II (AngII) induced activation of Calpain 10 24. Meanwhile previous studies have found significant increase of renal Angiotensin II (AngII) in DN 30,31.…”

Calpastatin prevents Angiotensin II–mediated podocyte injury through maintenance of autophagy

“…Indeed, calpastatin inhibits selectively calpains and no other proteases to date. Calpain activation has been linked recently to renal injury in several pathological contexts 69,70 . The calcium channel transporter Transient receptor potential channel C6 (TRPC6) was found to activate calpain-1 in podocyte via a Ca2+/calcineurin activation.…”