Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone-target gene expression.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or cirrhotic patients with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel b and g subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Cirrhotic patients showed increased expression of 11bHSD2, which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. We conclude that cirrhosis progression towards a decompensated state with hypovolemia induces remodeling of distal colon ion transporter expression to match a decaying kidney function, supporting a role for aldosterone in the process.