An update on novel mechanisms of primary aldosteronism

1. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 1

   Aldosterone biosynthesis in normal and pathological conditions. (A) ZG cells have a very high conductance for K⁺, which maintains a strongly negative membrane potential under resting conditions (−80 mV with normal plasma K⁺ concentrations) due to the expression of a large number of potassium channels. The concentration gradient of K⁺ between the intracellular and extracellular space that is required for the establishment of the membrane potential is generated by the activity of the Na⁺, K⁺-ATPase. Elevation of extracellular K⁺ concentration; decrease in intracellular K⁺ concentration; inhibition of the Na⁺, K⁺-ATPase, or potassium channels all lead to cell membrane depolarization, allowing opening of voltage-dependent Ca^{2 +} channels. (B) AngII acts through the AngII type 1 receptor (AT1R) to stimulate inositol trisphosphate-dependent Ca^{2 +} release from the endoplasmic reticulum. In addition, both AngII and K⁺ act by depolarizing the ZG cell membrane potential, leading to opening of voltage-gated Ca^{2 +} channels, which ultimately leads to an increase in intracellular Ca^{2 +} concentration. AngII triggers cell membrane depolarization by inhibiting potassium channels and the sodium potassium ATPase (Na⁺, K⁺-ATPase). Increased intracellular Ca^{2 +} concentration leads to the activation of the calcium signaling pathway, which triggers activation of specific transcription factors and positive regulation of CYP11B2 transcription. (C) Genetic alterations leading to cell membrane depolarization and intracellular ionic modification. KCNJ5 gain-of-function mutations affecting GIRK4 and ATP1A1 mutations of the Na⁺, K⁺-ATPase affect intracellular Na⁺ concentrations, leading to cell membrane depolarization triggering opening of voltage-gated Ca^{2 +} channels. Mutations in ATP2B3 coding for the plasma membrane Ca^{2 +}-ATPase PMCA3 and mutations in CACNA1D, affecting the Cav1.3 subunit of the L-type voltage-gated calcium channel, have direct consequences on intracellular Ca^{2 +} concentrations by affecting calcium recycling and influx. All genetic abnormalities ultimately lead to activation of Ca^{2 +} signaling and increased aldosterone biosynthesis. Full arrow, direct activation; hatched arrows, indirect activation requiring intermediary steps.
2. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 2

   (Upper panel) Three familial forms of PA have been described. FH1 is associated with a chimeric CYP11B1/11B2 gene, and FH3 with germline mutations in KCNJ5. FH2 is probably the most common form but without genetic abnormality identified so far. Germline de novo CACNA1D mutations have been identified in children with early-onset hypertension and hyperaldosteronism associated with a complex neurological disorder. Germline KCNJ5 variants have also been identified in a few cases of sporadic PA. Other Mendelian forms of familial hyperaldosteronism (FHx) may also exist. (Lower panel) In sporadic PA, recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 are found in >50% of APA. Other genes with point mutations or genomic rearrangements with loss of heterozygosity (LOH) have yet to be described. No mutation has been identified in BAH

• © 2015 Society for Endocrinology