Role of the α-, β-, and γ-Subunits of Epithelial Sodium Channel in a Model of Polygenic Hypertension

Abstract

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.

Recent Aspects in the Genetic Renal Mechanisms Involved in Hypertension.

“…Moreover, no differences are found in the mRNA levels of all three subunits in the kidneys of these strains. These observations do not support a crucial contribution of the epithelial sodium channel genes to blood pressure regulation in the polygenic hypertension of SHRSP (43).…”

Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

“…In an earlier study, Kreutz and coworkers failed to detect any changes in α-, β-, and γ-ENaC mRNA content in the kidneys of 16-week-old stroke-prone SHR (SHRSP) compared with normotensive WKY rats. 26 It should be underlined that Northern blotting in the cited study was hardly applicable to quantitative analysis. On the other hand, semiquantitative immunoblotting used by Kim and coworkers demonstrated an abundance of α-, β-, and γ-ENaC proteins in the cortex and outer medulla from 6-and 12-week-old SHR compared with WKY rats; animals aged >12 weeks were not included.…”

Isolation of a Chromosome 1 Region Affecting Blood Pressure and Vascular Disease Traits in the Stroke-Prone Rat Model

“…2 As far as linkage to BP is concerned, this locus has not been consistently documented among different colonies of SHRSP. 4,5 In SHRSP/Bbb, despite the significant linkage to stroke latency on RNO1, linkage to BP was not detectable until a gene-gene interaction (or epistasis) was taken into consideration between chromosome 1 and 10 regions. 4 In a Glasgow colony of SHRSP, SHRSP/Gg, on the other hand, linkage to BP has not been reported on RNO1 at all.…”

“…4,5 In SHRSP/Bbb, despite the significant linkage to stroke latency on RNO1, linkage to BP was not detectable until a gene-gene interaction (or epistasis) was taken into consideration between chromosome 1 and 10 regions. 4 In a Glasgow colony of SHRSP, SHRSP/Gg, on the other hand, linkage to BP has not been reported on RNO1 at all. 5 Here, it should be noted that WKY strains derived from respective colonies have been used as controls and that some degree of genetic heterogeneity is assumed to exist between them.…”