New role for plasmin in sodium homeostasis.
OBJECTIVE
Hypertension and edema are clinical manifestations of the extracellular volume expansion generated by abnormal renal sodium handling. Perturbations in epithelial sodium channel (ENaC) activity disrupt volume homeostasis. ENaC activity can be enhanced by proteases that cleave its long extracellular domains. Recent evidence suggests that this mechanism may be involved in individuals with volume overload and proteinuria.


RESULTS
Several observations indicate a link between proteinuria and hypertension, with proteinuria preceding and predicting the onset of incident hypertension in some individuals. Recently, enhanced cleavage of ENaC's extracellular loops was identified in kidney tissue of proteinuric mice. Plasmin, a serine protease known for its role in fibrinolysis, has been implicated as an activator of ENaC in proteinuric states as nephrotic urine activates ENaC expressed in a mouse collecting duct cell line, aprotinin-affinity precipitation of nephrotic urine abolishes its ability to activate ENaC, plasmin is a major component within aprotinin-affinity purified nephrotic urine and is absent in nonproteinuric urine, and plasmin activates ENaC by cleaving the extracellular loop of its gamma subunit.


CONCLUSIONS
Enhancement of ENaC activity by proteases represents a likely mechanism for extracellular volume overload relevant to some individuals with proteinuria. Proteases not normally found in the urine can enter the urinary space across damaged glomeruli and activate ENaC. Further understanding of this mechanism may guide targeted therapeutics in individuals with proteinuria, edema, and hypertension.
Passero
Christopher J
CJ
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. passcj@upmc.edu
Hughey
Rebecca P
RP
Kleyman
Thomas R
TR
D000818:Animals; D004487:Edema / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D011507:Proteinuria / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
D053503:Epithelial Sodium Channels; D012964:Sodium; D005341:Fibrinolysin