Epithelial Sodium Channel (ENaC) as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

Renal sodium retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome. There is abundant evidence that this occurs even in the absence of activation of hormones that are known to activate renal Na transporters. Proteinuria not only reflects glomerular damage, but also functions as a risk factor for cardiovascular disease, stroke, end stage renal disease and is associated with extracellular volume expansion and high BP. In the natural course of Type II diabetes, microalbuminuria and elevations in blood pressure are thought to occur at around the same time. Blood pressure in microalbuminuric diabetics is more sensitive to dietary salt intake than in normoalbuminuric patients despite both groups having similar aldosterone and plasma renin activity levels. Proteolytic processing of ENaC subunits might provide the primary defect in renal sodium handling in these microalbuminuric individuals. However, proteinuria is not consistently identified as a risk factor for incipient elevation in blood pressure and in some studies elevated blood pressure predicts the advent of microalbuminuria. Analyses of normotensive normoalbuminuric subjects in previous studies have found that higher urinary albumin levels in the normal range predicted incident hypertension. A similar finding was seen in a non-diabetic cohort. These studies suggest that these disparate results may be related to the cut off that defined microalbuminuria. Another possible explanation is that an ENaC activator, like plasmin, contributes to the generation of incident hypertension in some individuals. Levels of albuminuria may not necessarily be reflective of ENaC activator levels and may vary from individual to individual. Perhaps urinary plasmin and plasminogen provides a more robust biomarker for those individuals who may develop hypertension. Recent evidence suggests that in some individuals with glomerular damage, proteases not normally found in urine enter the urinary space and aberrantly cleave ENaC. In this setting, filtered plasminogen (inactive precursor) is converted to plasmin (active protease) by urokinase that is expressed in tubular epithelial lumen. The proteolytic activation of ENaC would generate a primary defect in renal sodium handling, a mechanism that may be a particularly important factor leading to increases in extracellular fluid volume and BP that accompany nephrotic syndrome. While previous studies have examined the role of amiloride in low-renin hypertension, and as an additional agent the conventional treatment of hypertension, no human trials have tested whether ENaC inhibitors impact blood pressure and volume status in the setting of proteinuria. Over a ten year period, millions of diabetics, 5.3% of Type II diabetics and 28% of Type I diabetics develop macroscopic proteinuria.