The Plot Thickens: Role of Plasmin in Edema Formation in Nephrotic Syndrome

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I was at the ASN Kidney Week in Philadelphia last week and I had the chance to check out some abstracts and discuss with the authors. Three abstracts called my attention right away. I uploaded a post a few months ago related to the mechanisms of edema in nephrotic syndrome (NS) : in patients with NS, plasminogen is filtered from plasma and activated in distal nephron by enzyme urokinase forming plasmin. Plasmin can then proteolytically activate ENaC by cleavage of the γ-subunit, leading to sodium retention and edema. These are the abstracts:
1. Abstract: [FR-PO1777] Urinary Content of Plasmin(ogen) and Activation of ENaC Current by Urine Resides during Remission of idiopathic Nephrotic Syndrome. Buhl et al.

The same group from University of Southern Denmark who published the original plasmin study came back again and presented more evidence for their hypothesis. They took spot urine samples from 20 children with active idiopathic NS and compared them to urine samples obtained after remission in the same patients. Urine samples were analyzed for plasmin and plasminogen concentrations and urinary protease activity. Urine plasmin and plasminogen concentrations (normalized to urine creatinine concentration) and urine protease activity were found to be significantly higher in the active phase of NS in comparison to the remission phase. Not only that, the urine samples obtained in the active phase were able to evoked stronger ENaC currents than the urine samples obtained in remission phase.

2. Abstract: [FR-PO1776] Preeclampsia Is Associated with Significant Urinary Excretion of Plasmin(ogen) and the Ability of Urine To Activate ENaC In Vitro. Buhl et al.

The same group above also did another study where urine samples from 16 preeclamptic patients and 17 normotensive, non-proteinuric pregnant women (control) matched on age and gestational age were compared. Urine was analyzed for plasminogen and proteolytic activity. ENaC currents after exposure to urine was monitored in M1 cells by whole cell patch clamp. Urine plasminogen concentration (normalized to urine creatinine concentration) and proteolytic activity were increased in the urine of preeclamptic patients but not in controls. What is more, a significant positive correlation was found in the preeclamptic group between urinary plasmin(ogen) and diastolic blood pressure. The ability of the urine samples from preeclamptic patients to evoke ENaC current was abolished by amiloride to a lower level than the controls, suggesting that there might be small amounts of plasmin (ogen) present in the urine under normal conditions. The authors speculated that this might have a natural anticoagulant effect in the urine.

3. Abstract: [FR-PO1779] Nephron Expression and Distribution of the Plasminogen Receptor, PLG-RKT, and Colocalization with ENaC and uPAR, in Murine Kidney. Nangia et al.

Dr. Parmer’s group at UCSD has identified the presence of a novel Plasminogen Receptor (PLG-RKT). This PLG-RKT, apparently colocalizes with urokinase, and ENaC on the apical surface of the distal nephron, and all of these are present in an orientation to promote Plasminogen activation and ENaC processing. They actually found that urokinase was also present in the proximal tubule but in a less prominent way than in the distal nephron. The significance of the latter is unknown. Therefore, the machinery for sodium retention is present even under normal conditions.

I believe these studies give more support to the Plasmin hypothesis.

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