Pendrin is upregulated by corticosterone and participates in its pressor response

NaCl restriction upregulates pendrin, in part, through increased circulating aldosterone and the intercalated cell (IC) mineralocorticoid receptor (MR). Since 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enhances aldosterone binding to this receptor in other cells, we asked if pendrin abundance is reduced in NaCl-restricted 11β-HSD2 knockout (KO) rats. However, pendrin abundance was greater in 11β-HSD2 KOs than in controls, possibly from enhanced glucocorticoid MR activation. Moreover, the MR antagonist, spironolactone, reduced pendrin abundance in mice that do not produce aldosterone (aldosterone synthase KO). IC MR gene ablation also reduced pendrin protein abundance in corticosterone-treated, adrenalectomized mice. Therefore, the MR regulates pendrin independently of aldosterone. As such, we asked whether glucocorticoids, the other MR ligands, change pendrin abundance and/or subcellular distribution in adrenalectomized wild-type mice. We observed that corticosterone upregulated pendrin in a dose-dependent manner through both increased total protein abundance and subcellular redistribution. At higher doses, corticosterone increased pendrin abundance from greater pendrin-positive cell number within the late distal convoluted tubule 2 (DCT2) rather than increased pendrin abundance per cell. Finally, we asked whether pendrin contributes to the hypertension seen in rodent models of Cushing syndrome. Although corticosterone increased blood pressure in wild-type mice, it had no effect in pendrin KOs. In conclusion, glucocorticoids upregulate pendrin by increasing pendrin total protein abundance through an MR-dependent pathway and subcellular redistribution. Glucocorticoids increase pendrin abundance by increasing the number of pendrin-positive cells within the DCT2. In doing so, pendrin contributes to the hypertension seen in rodent models of Cushing syndrome.<b>NEW & NOTEWORTHY</b> Pendrin participates in the hypertension seen in Cushing syndrome.