Pioglitazone belongs to the class of drugs called
thiazolidinediones (TZDs), which are widely used as
insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The
steroid hormone aldosterone also promotes
sodium and fluid retention; however, the effect of
pioglitazone on
aldosterone production is controversial. We analyzed the effect of
pioglitazone alone and in combination with
angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human
adrenocortical carcinoma HAC15 cells. Treatment with
pioglitazone for 24 h significantly increased the expression of
CYP11B2 and enhanced AngII-induced
CYP11B2 expression. Despite the observed changes in
mRNA levels,
pioglitazone significantly inhibited AngII-induced
aldosterone production and
CYP11B2 protein levels. On the other hand,
pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus,
pioglitazone promotes
CYP11B2 expression but nevertheless inhibits
aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast,
pioglitazone promoted AngII-induced
CYP11B1 expression and
cortisol production. Since
cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of
fatty acid oxidation, stimulate
cortisol secretion to promote utilization of
fatty acids during fasting. In turn, the ability of
pioglitazone to stimulate
cortisol production could potentially underlie the effects of this drug on fluid retention.