Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations

Abstract

BackgroundSomatic gene mutations that facilitate inappropriate intracellular calcium entrance have been identified in most aldosterone-producing adenomas (APAs). Studies suggest that angiotensin II and adrenocorticotropic hormone (ACTH) augment aldosterone production from APAs. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations.ObjectiveTo analyze the transcript expression of type 1 angiotensin II receptors (AGTR1), ACTH receptors (MC2R), and melanocortin 2 receptor accessory protein (MRAP) in APAs with known aldosterone-driver somatic mutations.MethodsRNA was isolated from APAs with mutations in: KCNJ5 (n = 14), ATP1A1 (n = 14), CACNA1D (n = 14), and ATP2B3 (n = 5), and from normal adjacent adrenal tissue (n = 45). Transcript expression of MC2R, MRAP, AGTR1, aldosterone synthase (CYP11B2), 17α-hydroxylase/17,20-lyase (CYP17A1), and 11β-hydroxylase (CYP11B1) were quantified using quantitative RT-PCR and normalized to β-actin.ResultsCompared to adjacent normal adrenal tissue, APAs had higher transcript levels of CYP11B2 (2,216.4 [1,112.0, 2,813.5]-fold, p < 0.001), MC2R (2.88 [2.00, 4.52]-fold, p < 0.001), and AGTR1 (1.80 [1.02, 2.80]-fold, p < 0.001]), and lower transcript levels of MRAP, CYP17A1, and CYP11B1 (0.28–0.36, p < 0.001 for all). MC2R and CYP11B2 transcripts were lower in APAs with KCNJ5 vs. other mutations (p < 0.01 for both). MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, and with MRAP expression in APAs harboring ATPase mutations.ConclusionsWhile MC2R and AGTR1 are expressed in all APAs, differences were observed based on the underlying aldosterone-driver somatic mutations. In tandem, our findings suggest that APAs with ATPase-mutations are more responsive to ACTH than KCNJ5-mutated APAs.

Adrenocorticotropic Hormone–Stimulated Adrenal Venous Sampling Underestimates Surgically Curable Primary Aldosteronism: A Retrospective Cohort Study and Review of Contemporary Studies

“…37 Conversely, some patients with an aldosterone-producing adenoma may demonstrate a robust increase in aldosterone secretion and hence lateralization index following ACTH, which may be attributed to differential expression of melanocortin type 2 receptor. 37,38 The response of cortisol itself to ACTH may also alter the lateralization index as many patients with primary aldosteronism demonstrate co-secretion of cortisol and other glucocorticoid metabolites. 39 Next-generation sequencing of adrenal tissue has afforded further insights into the molecular drivers of the differential response to ACTH in primary aldosteronism.…”

Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

“…Several genes encoding G-protein coupled receptors have been identified as differentially expressed in APAs, whereas a clear interrelation between GPCRs and physiological aldosterone secretion is acknowledged for the Melanocortin 2 Receptor ( MC2R ) and the 5-Hydroxytryptamine Receptor ( 5-HTR-4 ). In several studies, Luteinizing Hormone/Choriogonadotropin Receptor ( LHCGR ), Gonadotropin Releasing Hormone Receptor ( GNRHR ), 5-HTRs 2A and 4, Angiotensin II Receptor Type 1 ( AGTR1 or AT1R ), Glutamate Metabotropic Receptor 3 ( GRM3 ), Endothelin Receptor Type B ( EDNRB ), MC2R , and Prostaglandin E Receptor 1 ( PTGER1 ), among others, were all found to be significantly upregulated in APAs [ 50 , 70 , 71 , 72 ]. In one recent study, MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, whereas MC2R expression correlated positively with Melanocortin 2 Receptor Accessory Protein ( MRAP ) only in ATP1A1 - and ATP2B3 -mutated APAs [ 72 ].…”

“…In several studies, Luteinizing Hormone/Choriogonadotropin Receptor ( LHCGR ), Gonadotropin Releasing Hormone Receptor ( GNRHR ), 5-HTRs 2A and 4, Angiotensin II Receptor Type 1 ( AGTR1 or AT1R ), Glutamate Metabotropic Receptor 3 ( GRM3 ), Endothelin Receptor Type B ( EDNRB ), MC2R , and Prostaglandin E Receptor 1 ( PTGER1 ), among others, were all found to be significantly upregulated in APAs [ 50 , 70 , 71 , 72 ]. In one recent study, MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, whereas MC2R expression correlated positively with Melanocortin 2 Receptor Accessory Protein ( MRAP ) only in ATP1A1 - and ATP2B3 -mutated APAs [ 72 ]. Moreover, LHCG - and GNRH -receptor upregulation were both correlated with APAs harboring CTNNB1 mutations [ 12 , 49 ].…”

Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism

“…[46][47][48] This dichotomy of responses is currently under intense investigation and has been suggested to reflect the cellular composition of the tumor, 46,49 the mutational status of aldosterone driver genes, 50 and/or ectopic/heterogeneous receptor expression. [51][52][53] In vivo zG-TASK-LOF mice display a mild-hyperaldosteronism with a component of aldosterone autonomy. In this disease model, AT 1 R antagonism or high sodium dietary intake reduces aldosterone production yet neither treatment normalizes elevated urinary aldosterone excretion to that of WT mice.…”