Mechanisms of sodium retention in nephrotic syndrome :

Data are limited with regard to the relations of low-grade albuminuria (below the microalbuminuria threshold) and incidence of cardiovascular disease (CVD) events in nondiabetic, nonhypertensive individuals. We examined the association of urinary albumin excretion (spot urine albumin indexed to creatinine [UACR]) and the incidence of CVD events and all-cause mortality in 1568 nonhypertensive, nondiabetic Framingham Offspring Study participants (mean age, 55 years; 58% women) free of CVD. On follow-up (median, 6 years), 54 participants (20 women) developed a first CVD event, and 49 (19 women) died. After adjustment for established risk factors, increasing UACR was associated with greater risk of CVD (hazards ratio [HR] per SD increment in log UACR, 1.36; 95% CI, 1.00 to 1.87) and death (HR per SD increment in log UACR, 1.55; 95% CI, 1.10 to 2.20). Participants with UACR greater than or equal to the sex-specific median (> or =3.9 microg/mg for men, > or =7.5 microg/mg for women) experienced a nearly 3-fold risk of CVD (adjusted HR, 2.92; 95% CI, 1.57 to 5.44; P<0.001) and a borderline significantly increased risk of death (adjusted HR, 1.75; 95% CI, 0.95 to 3.22; P=0.08) compared with those with UACR below the median. The increased CVD risk associated with UACR at or above the median remained robust in analyses restricted to individuals without microalbuminuria (n=1470) and in subgroups with intermediate (n=1469) and low (n=1186) pretest probabilities of CVD. In our community-based sample of middle-aged nonhypertensive, nondiabetic individuals, low levels of urinary albumin excretion well below the current microalbuminuria threshold predicted the development of CVD. Our observations add to the growing body of evidence that challenges the notion that UACR <30 microg/mg indicates "normal" albumin excretion.

Epithelial Na(+) channels (ENaCs) are activated by extracellular trypsin or by co-expression with channel-activating proteases, although there is no direct evidence that these proteases activate ENaC by cleaving the channel. We previously demonstrated that the alpha and gamma subunits of ENaC are cleaved during maturation near consensus sites for furin cleavage. Using site-specific mutagenesis of channel subunits, ENaC expression in furin-deficient cells, and furin-specific inhibitors, we now report that ENaC cleavage correlates with channel activity. Channel activity in furin-deficient cells was rescued by expression of furin. Our data provide the first example of a vertebrate ion channel that is a substrate for furin and whose activity is dependent on its proteolysis.

Sodium balance, and ultimately blood pressure and extracellular fluid volume, is maintained by precise regulation of the activity of the epithelial sodium channel (ENaC). In a Xenopus kidney epithelial cell line (A6), exposure of the apical membrane to the protease inhibitor aprotinin reduces transepithelial sodium transport. Sodium-channel activity can be restored by subsequent exposure to the nonspecific protease trypsin. Using A6 cells and a functional complementation assay to detect increases in ENaC activity, we have cloned a 329-residue protein belonging to the serine protease family. We show that coexpression of this protein with ENaC in Xenopus oocytes increases the activity of the sodium channel by two- to threefold. This channel-activating protease (CAP1) is expressed in kidney, gut, lung, skin and ovary. Sequence analysis predicts that CAP1 is a secreted and/or glycosylphosphatidylinositol-anchored protein: ENaC activity would thus be regulated by the activity of a protease expressed at the surface of the same cell. This previously undiscovered mechanism for autocrine regulation may apply to other ion channels, in particular to members of the ENaC family that are present in neurons and epithelial cells.