(731.6) Transcriptional response of aldosterone target genes in the rat and human distal colon during hepatic cirrhosis

Poster Board Number: E240

Diego Alvarez de la Rosa (Universidad de La Laguna, Universidad de La Laguna), Natalia Serrano-Morillas (Universidad de La Laguna), Carlos González-Alayón (Hospital Universitario de Canarias), Huma Shehwana (Bilkent University), Ozlen Konu (Bilkent University), Manuel Hernández-Guerra (Universidad de La Laguna, Hospital Universitario de Canarias)

Hepatic cirrhosis is associated to circulatory abnormalities. A combination of vasodilation, lower plasmatic protein content and splanchnic venous stagnation leads to hypovolemia, which in turn stimulates the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure and subsequent impaired K+ 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 hepatic cirrhosis. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included new aldosterone-regulated genes identified via whole transcriptome analysis. Our comparison revealed that multiple aldosterone-target genes are upregulated during cirrhosis in the rat distal colon. This upregulation is more prominent in animals showing decompensated cirrhosis. Epithelial Na+channel (ENaC) β and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Altogether, our results demonstrate cirrhosis-induced ion transporter subunit expression remodeling, a change that correlated well with the severity of the disease and suggested a role for aldosterone in the process. The expression of a subset of these genes was then tested in distal colon biopsies obtained from patients showing decompensated cirrhosis and treated or not with mineralocorticoid receptor inhibitor spironolactone. Preliminary results show decreased expression of ENaC subunits and channel regulator K-ras in patients treated with spironolactone. 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.

This work was supported by grants BFU2016-78374-R and PID2019-105339RB-I00 to D.A.d.l.R., funded by MCIN/AEI/10.13039/501100011033 and amp;ldquo;ERDF A way of making Europeamp;rdquo;. N.S.-M. was supported by fellowship BES-2014-068280, funded by MCIN/AEI/10.13039/501100011033 and amp;ldquo;ESF Investing in your futureamp;rdquo;.