PS 04-04 COMPUTATIONAL ANALYSIS OF THE EFFECTS OF ALDOSTERONE AND METABOLIC ACIDOSIS ON GENE EXPRESSIONS IN RENAL TUBULES

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Abstract

Objective:

Renin-angiotensin-aldosterone system (RAAS) blockers are the first-line agent to treat patients with chronic kidney disease (CKD). Although RAAS blockers slow CKD progression, they sometimes cause metabolic acidosis as an adverse effect, which possibly worsens CKD. We investigated metabolic acidosis-induced, but aldosterone-independent, kidney injury by discovering gene expressions in renal tubules.

Design and Method:

We searched publications and picked up known gene transcripts that are induced in epithelial cells in the kidney either by administration of aldosterone or acid loading. To discover aldosterone-stimulated gene transcripts, we examined transcriptional start site-sequencing using a rat intercalated cell line (IN-IC cells), and then added newly found aldosterone-stimulated gene transcripts to the gene lists. Using DAVID Bioinformatics Database, we examined Gene Ontology (GO) analysis for the gene transcripts. Using oPOSSUM, we analyzed promoter regions of the genes and estimated enriched consensus motifs in the promoters of the genes.

Results:

Among publications and our experiments, 64 and 105 genes were picked up for aldosterone- and acid-stimulated genes, respectively. Only 5 genes were overlapped between two stimulations. GO analysis indicated 5 common GO terms in molecular function and biological process between two stimulations such as regulation of blood pressure, ATPase activity, and ion transport. Acid-stimulated genes indicated specific GO terms such as oxidative stress and protein catabolic process. The promoter analysis raised 27 and 21 consensus motifs for aldosterone- and acid-induced genes, respectively (Z-score > 5.0). There were 4 motifs overlapped between two stimulations, which include the hormone response element, a target of mineralocorticoid receptor (MR). Specific motifs for acid-induced genes include the motifs for Ets and NFAT TF families, and they locate on the promoter region of ATP6AP2 (Prorenin receptor).

Conclusions:

The results suggest that metabolic acidosis induced by RAAS blockers could stimulate many aldosterone-independent genes in renal tubules, which may affect blood pressure and CKD progression.

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