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Minimal change-like glomerular alterations induced by a human plasma factor
P K Cheung1, P A Klok, W W Bakker
1Department of Pathology, University of Groningen, The Netherlands.
Abstract:
Circulating factors, including the plasma protease (100 KF) described previously, have been suspected to play a role in the pathogenesis of minimal change disease (MCD) for several decades. This factor was able to induce MCD-like alterations in kidney tissue in vitro, i.e. impairment of glomerular polyanion (GPA), as well as glomerular ecto-ATPase. We conducted permeability studies using alternate perfusion of the rat kidney ex vivo according to standard techniques. Either native 100 KF (n = 7) or control factor (n = 7) perfusion, followed by perfusion with diluted rat serum was carried out, while urine samples were collected by ureter cannulation. Total urinary protein (by spectrophotometry) as well as IgG (by ELISA) and albumin (by rocket electrophoresis) were measured. Sections of perfused kidneys were stained (immuno-) histochemically for GPA and glomerular ecto-ATPase, and the stainability was quantified using image analysis and expressed as arbitrary units. The results show significantly increased protein leakage after perfusion of 100 KF versus control factor (150.0 +/- 48.9 vs. 33.2 +/- 7.7 micrograms/min, p < or = 0.01), while the IgG/albumin ratio has decreased (12.0 +/- 9.4 vs 26.9 +/- 14.4%, p < or = 0.01). Plasma protein leakage after 100KF perfusion is associated with a significant loss of GPA (57.3 +/- 27.5 vs. 98.4 +/-12.0, p < or = 0.01) and significant decrease of glomerular ecto-ATPase expression (28.7 +/- 11.5 vs. 79.5 +/- 15.0, p < or = 0.001). The capability of 100KF to induce MCD-like glomerular lesions, in association with selectively increased permeability for plasma proteins, suggests that this human plasma constituent may be important in the pathogenesis of MCD.
Insights
A specific plasma protease, 100 KF, significantly increases protein leakage in kidneys, mimicking minimal change disease (MCD). This factor impairs glomerular polyanion and ecto-ATPase, suggesting its role in MCD pathogenesis.
Area of Science:
- Nephrology
- Pathophysiology
- Biochemistry
Background:
- Minimal change disease (MCD) pathogenesis is linked to circulating factors.
- A plasma protease, termed 100 KF, has been implicated in MCD.
- Previous in vitro studies suggested 100 KF induces MCD-like kidney alterations.
Purpose of the Study:
- To investigate the in vivo effect of 100 KF on kidney permeability and protein leakage.
- To assess the impact of 100 KF on glomerular polyanion (GPA) and glomerular ecto-ATPase.
- To determine if 100 KF can induce minimal change disease-like lesions in ex vivo perfused rat kidneys.
Main Methods:
- Ex vivo perfusion of rat kidneys with either native 100 KF or a control factor.
- Collection of urine samples for measurement of total protein, IgG, and albumin.
- Histochemical and immunohistochemical staining of kidney sections for GPA and glomerular ecto-ATPase, quantified by image analysis.
Main Results:
- Perfusion with 100 KF significantly increased urinary protein leakage compared to control (150.0 vs. 33.2 µg/min).
- The IgG/albumin ratio decreased significantly after 100 KF perfusion (12.0% vs. 26.9%).
- 100 KF perfusion led to significant loss of GPA (57.3 vs. 98.4 arbitrary units) and reduced glomerular ecto-ATPase expression (28.7 vs. 79.5 arbitrary units).
Conclusions:
- The 100 KF factor induces minimal change disease-like glomerular lesions in ex vivo perfused rat kidneys.
- Increased plasma protein permeability is associated with GPA loss and reduced glomerular ecto-ATPase expression.
- This human plasma constituent, 100 KF, is a potential key factor in the pathogenesis of minimal change disease.