Sodium retention and volume expansion in nephrotic syndrome: implications for hypertension

Abstract

Sodium retention is a major clinical feature of nephrotic syndrome. The mechanisms responsible for sodium retention in this setting have been a subject of debate for years. Excessive sodium retention occurs in some individuals with nephrotic syndrome in the absence of activation of the renin-angiotensin-aldosterone system, suggesting an intrinsic defect in sodium excretion by the kidney. Recent studies have provided new insights regarding mechanisms by which sodium transporters are activated by factors present in nephrotic urine. These mechanisms likely have a role in the development of hypertension in nephrotic syndrome, where hypertension may be difficult to control, and provide new therapeutic options for the management of blood pressure and edema in the setting of nephrotic syndrome.

Keywords: Epithelial sodium channel; Nephrotic syndrome; Potassium sparing diuretics; Proteinuria; Serine proteases.

Figure 1

Two of ENaC’s three subunits (α and γ) undergo proteolytic cleavage. Furin cleaves the channel before it reaches the cell surface (closed arrowheads). Some channels escape furin cleavage and arrive at the cell surface intact. These channels exhibit very low activity, or open probability (P_o). Furin cleaves the α subunit twice and the γ subunit once. Dual cleavage of the α subunit by furin releases that subunit’s inhibitory tract, resulting in channels with intermediate activity. The γ subunit harbors one furin cleavage site proximal to its inhibitory tract, and sites for various other extracellular proteases distal to the inhibitory tract (open arrowhead). Release of the γ subunit inhibitory tract occurs when the subunit has been cleaved by both furin and a second protease, resulting in a maximally activated channel.