Plasmin and Sodium Retention in Nephrotic Syndrome
Thomas R. Kleyman and
Rebecca P. Hughey
Renal-Electrolyte Division, Department of Medicine, and Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
Correspondence: Dr. Thomas R. Kleyman, Renal-Electrolyte Division, University of Pittsburgh, A919 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: 412-647-3121; Fax: 412-648-9166; E-mail: kleyman{at}pitt.edu
Epithelial Na+ channels (ENaC) are found within the most distalaspects of the nephron, where they serve as a final arbitratorof the reabsorption of filtered Na+. This process has a criticalrole in the regulation of extracellular fluid volume and BP.Edema-forming states, including cirrhosis, heart failure, andnephrotic syndrome, are associated with enhanced renal Na+ absorption.Aldosterone has a role in renal Na+ retention in these disorders;however, Na+ retention in nephrotic syndrome as a result ofactivation of Na+ absorptive processes in the distal nephronmay occur by aldosterone-independent mechanisms.1,2
A number of factors that activate ENaC have been described,including cleavage of ENaC subunits by proteases.3 The and subunits are cleaved by proteases in specific regions withintheir extracellular domains. By cleaving subunits at least twice,inhibitory tracts are released and channels are activated.4,5ENaC is moderately activated when cleaved by furin, a proteasethat resides in the trans-Golgi network, as the subunit iscleaved twice by furin releasing an inhibitory tract. In contrast,the subunit is cleaved only once by furin. A second cleavageevent distal to the subunit furin site is needed to activatethe channel fully.5–7 Studies by Svenningsen et al.8 inthis issue of JASN, as well as recent work from our group,9provide evidence that plasmin may function as the second proteasethat cleaves the subunit and activates ENaC in the settingof nephrotic syndrome.
Both plaminogen and plasmin are present in nephrotic urine,8–10suggesting that plasminogen is filtered by a damaged glomerulus.Plasminogen is cleaved to its active form, plasmin, by variousproteases, including urokinase. The presence of urokinase withinthe tubular lumen of the nephron facilitates the processingof filtered plasminogen to an active form.8,11,12 Plasmin joinsa growing list of proteases that cleave the subunit at sitesdistal to the furin cleavage site and activates ENaC in associationwith release of an inhibitory tract.3,5,13
These observations provide new insights regarding a mechanismfor renal Na+ retention in nephrotic syndrome. They also raisea number of questions that will need to be addressed in futurestudies. Because amiloride inhibits both ENaC and urokinase,is it effective in ameliorating renal Na+ retention and volumeexpansion in nephrotic syndrome in humans? If plasmin is theactivation culprit, then are renal Na+ retention and volumeexpansion in nephrotic syndrome prevented by plasmin inhibitorsor by a lack of plasminogen expression (plasminogen knockoutmouse model)? Although nephrotic syndrome occurs in the settingof various disorders, is the presence of plaminogen and plasminin the urine a common finding, or is it restricted to subsetsof individuals with nephrotic syndrome? Are there other clinicaldisorders whereby disease-specific proteases cleave and activateENaC? With regard to this last question, enhanced ENaC proteolysismay contribute to enhanced ENaC activity in the airways of individualswith cystic fibrosis.14,15
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Introduction
DISCLOSURES
and 
subunits are cleaved by proteases in specific regions within their extracellular domains. By cleaving subunits at least twice, inhibitory tracts are released and channels are activated.4,5 ENaC is moderately activated when cleaved by furin, a protease that resides in the trans-Golgi network, as the 
