Increased renal ENaC subunits and sodium retention in rats with chronic heart failure

Abstract

Renal tubular dysfunction could be involved in the increased sodium and water reabsorption in chronic heart failure (CHF). The goal of the present study was to examine the molecular basis for the increased renal sodium and water retention in CHF. We hypothesized that dysregulation of renal epithelial sodium channels (ENaC) could be involved in the pathogenesis of CHF. The left coronary ligation-induced model of heart failure in the rat was used. Real-time PCR and Western blot analysis indicated that the mRNA and protein abundance of α-, β-, and γ-subunits of ENaC were significantly increased by in the cortex (mRNA: α-ENaC Δ104 ± 24%, β-ENaC Δ47 ± 16%, γ-ENaC Δ55 ± 18%; protein: α-ENaC Δ114 ± 28%, β-ENaC Δ150 ± 31%, γ-ENaC Δ39 ± 5% compared with sham rats) and outer medulla (mRNA: α-ENaC Δ52 ± 18%, β-ENaC Δ38 ± 8%, γ-ENaC Δ39 ± 13%; protein: α-ENaC Δ88 ± 16%, β-ENaC Δ94 ± 28%, γ-ENaC Δ45 ± 9% compared with sham rats) of CHF compared with sham-operated rats. Immunohistochemistry microscopy confirmed the increased labeling of α-, β-, and γ-ENaC subunits in the collecting duct segments in rats with CHF. Furthermore, there was a significant increase in diuretic (7-fold compared with sham) and natriuretic responses (3-fold compared with sham) to ENaC inhibitor benzamil in the rats with CHF. Absence of renal nerves produced a greater contribution of ENaC in sodium retention in rats with CHF. These results suggest that the increased expression of renal ENaC subunits may contribute to the renal sodium and water retention observed during CHF.

Clues to renal sodium retention

“…Thus, even with a modest increase in the pool of channels at the plasma membrane, proteolytic cleavage of the ␣-and ␥-subunits could lead to a significant increase in sodium absorption in the aldosterone-sensitive distal nephron. As mentioned above, the functional responses to benzamil were increased three-to fourfold in CHF rats compared with controls, whereas ENaC subunit transcripts and proteins were only increased up to twofold (31). One possible interpretation is that perhaps there are greater amounts of the processed forms of the ␣-and ␥-subunits in the CHF condition.…”

“…In conclusion, the article by Zheng et al (31) provides important insights to sodium and fluid retention in CHF. This study suggests that ENaC contributes to sodium retention and extracellular volume overload seen in CHF patients.…”

“…These results suggested that in addition to the renal nerves, there also might be other factors that are involved in sodium retention during CHF. Zheng et al (31) now report that renal denervation increases diuresis and natriuresis in rats, even though these parameters were not affected by benzamil (31). The results suggest that ENaC activity is relatively low in rats kept on a normal sodium diet and that renal denervation by itself does not have an effect on basal ENaC activity.…”

“…It is conceivable that in the absence of a large change in the total pool of channels, elevated levels of systemic AVP may increase the abundance of channels at the apical membrane of CHF rats. Dysregulation of the renin-angiotensinaldosterone system also has been suggested as a major contributor of sodium retention in CHF, and it may account for the observed difference among ENaC protein expression and ENaC functional activity in the study by Zheng et al (31). Aldosterone promotes the transcription and translation of ENaC subunit genes and proteins, enhances proteolytic cleavage of the ␣-and ␥-subunits (13), and increases delivery of channels to the plasma membrane (2,17), which ultimately results in an increase in the number of active channels at the plasma membrane (15,19).…”

“…ENaCs are assembled as trimers composed of three structurally related subunits termed ␣, ␤, and ␥ (8, 14). Zheng et al (31) present compelling evidence that ENaC dysregulation contributes to sodium retention in CHF. They found that ENaC subunit transcripts and proteins were increased up to twofold, whereas ENaC-mediated sodium absorption was increased about threeto fourfold in CHF rats compared with control rats.…”