Primary aldosteronism (PA) is the most common type of secondary hypertension occurring in ∼10% of hypertensive patients. Up to 50% of PA is caused by aldosterone-producing adenomas (APA). This study is to identify the potential biological processes and canonical pathways involved with aldosterone regulation, APA formation, or APA and ZG cell functions.Design and Method:
Gene ontology (GO) and pathway analyses were performed on genes differentially expressed in APAs when compared to ZG and on genes differentially expressed in ZG when compared to ZF. Comparisons were also made between KCNJ5 genotypes.Results:
The most significantly enriched canonical pathway was ’NRF2-mediated oxidative stress response’ in APA vs. ZG (P = 7.87 × 10−5). The main molecular and cell functions of the differentially expressed genes in APA vs. ZG included cell death and survival, cellular growth and proliferation, cellular movement, lipid metabolism and small molecule biochemistry. In ZG vs. ZF, the most significantly enriched canonical pathway of the up-regulated genes was ’Wnt/β-catenin signaling’ (P = 2.13 × 10−5) and the most upstream regulating gene was TGFB1 (P = 3.80 × 10−14). The main molecular and cell functions of the differentially expressed genes in ZG vs. ZF included lipid metabolism, small molecule biochemistry, vitamin and mineral metabolism, cell death and survival and molecular transport. The canonical pathways enriched in both APA and ZG, were ‘NRF2-mediated Oxidative Stress Response’ and ‘LPS/IL-1 Mediated Inhibition of RXR Function’ (Figure 1). Comparing the genotypes of KCNJ5, two of the top three molecular and cell functions (cellular development, cell death and survival) associated with the differentially expressed genes in KCNJ5 mutant APAs vs. wild-type APAs, were also the top ones in KCNJ5 mutant ZF vs. wild-type ZF.Conclusions:
We have identified potentially novel mechanisms for APA and ZG cell function that could provide insights into pathological and physiological aldosterone regulation and APA formation.