A physician is managing a 45-year-old female patient who presents with resistant hypertension and spontaneous hypokalemia. Diagnostic testing reveals an elevated plasma aldosterone concentration to plasma renin activity ratio, and abdominal imaging confirms a unilateral adrenal adenoma. The patient's condition results in excessive sodium reabsorption in the distal nephron. Arrange the following cellular events in the correct chronological sequence to describe the physiological mechanism of action for the hormone overproduced in this condition.
- 1Diffusion of the lipophilic hormone across the basolateral cellular membrane
- 2Binding to the cytosolic mineralocorticoid receptor and dissociation of chaperone proteins
- 3Translocation of the activated hormone-receptor complex into the nucleus
- 4Transcription of target genes including serum and glucocorticoid-regulated kinase 1 (SGK1)
- 5Phosphorylation of target proteins leading to ENaC insertion into the apical membrane
Answer
The correct sequence begins with the hormone entering the cell via diffusion, followed by cytosolic receptor binding, nuclear translocation, gene transcription, and finally the insertion of sodium channels into the membrane.
Aldosterone is a lipophilic steroid hormone that exerts its effects primarily via a genomic mechanism. First, it diffuses across the basolateral membrane of the principal cells in the renal collecting duct. Second, it binds to the cytosolic mineralocorticoid receptor, inducing a conformational change and the shedding of associated chaperone proteins. Third, this active complex translocates into the nucleus. Fourth, it binds to specific DNA sequences to promote the transcription of aldosterone-induced proteins, particularly SGK1. Finally, SGK1 inhibits the ubiquitin ligase Nedd4-2, preventing the degradation of epithelial sodium channels (ENaC) and resulting in their increased insertion into the apical membrane.
Step-by-Step Solution
Key Concept
Steroid hormone mechanism of action (Aldosterone)