Investigation of Molecular Mechanisms Associated With Primary Aldosteronism Based on Transcriptome Sequencing

Abstract

Background: Primary aldosteronism (PA) is a common cause of secondary hypertension. Despite considerable advances in medical sciences, the underlying molecular mechanisms of PA remain inadequately investigated. Therefore, this study aims to identify potential therapeutic targets for PA by using transcriptome sequencing, providing promising insights for early diagnosis and precise management of this condition. Methods: Transcriptomic sequencing was performed on blood samples from PA patients and healthy controls. DESeq2 identified differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) of DEGs identified core module genes, which underwent functional enrichment for significant pathways and target detection. Subsequently, aldosterone-producing adenoma (APA) rat models were established. Potential targets (e.g., tuberous sclerosis complex 2 (<i>TSC2</i>)) were modulated via overexpression or shRNA interference, with effects validated physiologically, cellularly, and molecularly. Results: Our analysis identified 277 DEGs and 8 functional modules. Eigengenes in the pink module exhibited the strongest association with disease clinical phenotypes. The genes within this module were significantly enriched in the mammalian target of rapamycin (mTOR) signaling pathway, with <i>TSC2</i> identified as a central hub gene, indicating its potential as a promising therapeutic target for PA. In APA rats, TSC2 overexpression significantly inhibited plasma aldosterone (ALD) increase (<i>p</i> < 0.0001) and elevated plasma renin activity (PRA) (<i>p</i> < 0.001). Furthermore, it inhibited adrenal cell proliferation (<i>p</i> < 0.0001), reduced S-phase fraction (<i>p</i> < 0.0001), decreased Ki67 (<i>p</i> < 0.0001), and increased p21 expression (<i>p</i> < 0.01). Western blot analysis revealed that TSC2 overexpression reduced the adrenal p-mTOR/mTOR ratio (<i>p</i> < 0.0001), while increasing p-eukaryotic translation initiation factor 4E-binding protein (p-4EBP)/4EBP (<i>p</i> < 0.001) in APA rats. Conversely, sh-TSC2 knockdown produced opposing patterns. Conclusions: Transcriptome analysis identified <i>TSC2</i> as a promising therapeutic target for PA, which was later confirmed in rat models. <i>TSC2</i> likely alleviates PA by inhibiting mTOR pathway activation, thereby reducing abnormal adrenal cell proliferation and aldosterone secretion.