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No complement receptor 1 stumps on podocytes in human glomerulopathies
1Departments of Pathology and Research, Basel Medical School, Basel, Switzerland.
Insights
Complement receptor type 1 (CR1) loss in podocytes is not due to proteolysis but decreased synthesis in glomerulopathies. This reduced CR1 synthesis may increase podocyte susceptibility to complement-mediated damage.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Type one complement receptor (CR1) is the sole physiological complement inhibitor on podocytes.
- CR1 deficiency is observed in various glomerulopathies, notably lupus nephritis.
- Proteolytic cleavage of CR1 from podocyte membranes has been hypothesized as the cause of loss.
Purpose of the Study:
- To investigate if CR1 proteolytic cleavage on podocytes is a widespread phenomenon across different glomerulopathies.
- To determine the mechanism behind CR1 loss in podocytes.
Main Methods:
- Utilized monoclonal and polyclonal antibodies targeting extracellular and intracellular CR1 epitopes, respectively.
- Applied antibodies to sequential serial sections of renal biopsies from patients with various glomerulopathies.
- Analyzed CR1 expression patterns in normal and diseased glomeruli.
Main Results:
- Normal glomeruli showed consistent CR1 expression with both antibodies.
- Reduced expression of both extracellular and intracellular CR1 portions was observed in lupus nephritis, FSGS, IgA nephritis, membranous glomerulonephritis, and minimal change disease.
- A strong correlation (rs = 0.951, P < 0.001) was found between the decreased expression of extracellular and intracellular CR1 portions, confirmed in focal glomerular lesions.
Conclusions:
- Podocytes do not exhibit CR1 stumps, refuting the proteolytic cleavage hypothesis.
- CR1 loss in podocytes is attributed to diminished synthesis rather than consumption.
- Reduced CR1 synthesis may heighten podocyte vulnerability to complement-mediated injury.
Background:
Type one complement receptor (CR1) is the only physiological inhibitor of complement on podocytes. CR1 is lost in different glomerulopathies, in particular in lupus nephritis, in which it has been suggested that CR1 is removed by proteolysis from the cell membrane.
Methods:
To define whether proteolytic cleavage of CR1 on podocytes is a general phenomenon, we analyzed the expression of CR1 in different glomerulopathies using a monoclonal antibody against epitopes present on the extracellular portion of the molecule and a polyclonal antibody directed at the intracellular tail of CR1. The two antibodies were applied on sequential serial histologic sections of renal biopsy.
Results:
In normal glomeruli, the two antibodies provided similar results, that is, strong staining of podocytes, and both were shown to recognize specifically CR1. Decreased expression of the extracellular portion of CR1 was observed in lupus nephritis (8/8), focal and segmental glomerulosclerosis (FSGS; 7/7), IgA nephritis (6/6), membranous glomerulonephritis (3/3), and minimal change disease (3/3). In each case, the decreased expression was accompanied by a simultaneous decrease of the expression of the intracellular tail of CR1 (Spearman's correlation coefficient rs = 0.951, P < 0.001). This observation was confirmed by analyzing focal glomerular lesions on sequential serial sections.
Conclusion:
These data indicate that there are no CR1 stumps on podocytes, even in lupus nephritis, and suggest that the CR1 loss on podocytes is not due to consumption but to decreased synthesis. A loss of CR1 synthesis might render podocytes highly sensitive to complement attack.