Alternative splicing regulation of the epithelial sodium channel (ENaC) in Dahl rats

Title: Alternative splicing regulation of the epithelial sodium channel (ENaC) in Dahl rats
Authors: Shehata, Marlene Fouad Amin
Date: 2010
Abstract: The epithelial sodium channel (ENaC) is critical in controlling the rate of renal sodium reabsorption and maintaining long term blood pressure control. ENaC activity is twice as high in kidneys of high salt-fed Dahl salt-sensitive (S) rats versus a sister salt-resistant strain (Dahl R), which might explain the increased blood pressure in high salt-fed Dahl S rats versus R rats. ENaC blockade in the brain by benzamil rescued Dahl S rats from salt-induced hypertension. The aims of the present study were: (i) To test whether Dahl S rats harbor genetic polymorphisms in the ENaC alpha, beta, and/or gamma genes that might contribute to their enhanced ENaC activity; (ii) To investigate whether alpha ENaC in Dahl rats' kidney is associated with alternatively spliced forms, and their corresponding mRNA levels, should they exist, in Dahl S versus R rats on normal and high salt diet; (iii) To examine the putative biological function of alpha ENaC alternatively spliced forms when co-expressed with alpha ENaC-wt. The first comprehensive sequence analysis of ENaC genes did not reveal any differences between Dahl S and R rats that were isogenic in the entire coding regions, exon-intron junctions, 3' and 5' flanking regions of ENaC alpha, beta, and gamma genes. Two coding (a and b) and two non coding (c and d) alpha ENaC alternatively spliced forms were identified whose mRNA levels were elevated in Dahl R versus S rats. Among the four alpha ENaC transcripts, the salt-sensitive alpha ENaC-b was highly abundant exceeding alpha ENaC-wt abundance by ∼32 fold. The translated alpha ENaC-b protein sequestered alpha ENaC-wt and reduced alpha ENaC-wt expression in a dose-dependent manner. Increased ENaC activity in Dahl S versus R rats might be attributed to the lower abundance of alpha ENaC-b, a dominant negative expression regulator of alpha ENaC.
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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