Related Experiment Videos
Glomerular macrophages and the mesangial proliferative response in the experimental nephrotic syndrome
1Department of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033.
Abstract:
Mesangial cell proliferation, which is a harbinger of glomerulosclerosis, occurs in both immune and nonimmune glomerulopathies. The proximity of infiltrating glomerular macrophages to the contractile mesangial cells during acute puromycin aminonucleoside (PA) nephrosis suggests the possibility of a paracrine effect on mesangial cell growth. To test this, three maneuvers to either raise or lower the glomerular macrophage number during acute PA nephrosis (2 weeks after PA) were employed: 1) an essential fatty acid-deficient (EFAD) diet; 2) a cholesterol-supplemented diet (CSD); and 3) a single dose (600 rad) whole-body X-irradiation (XI) given to CSD-fed PA rats. Both the glomerular macrophage number and proliferation within the mesangium were evaluated immunohistochemically with ED-1, a mouse monoclonal anti-rat macrophage label, and 19A2, a mouse monoclonal anti-proliferating cell nuclear antigen (PCNA)/cyclin antibody, respectively. Immunohistochemical detection of 5'-bromo-2'-deoxyuridine (BrdU) incorporation confirmed that proliferation was occurring within the mesangial zones. The EFAD diet significantly reduced both the glomerular macrophage and PCNA/cyclin-positive cell number at 2 weeks after PA with a positive correlation (r = 0.89, P < 0.05). The CSD maneuver significantly increased both the glomerular macrophage and PCNA/cyclin cell number with a strong degree of correlation (r = 0.95, P < 0.01). X-irradiation administered to CSD-fed PA rats significantly lowered both the glomerular macrophage and PCNA/cyclin-positive cell number at 2 weeks. In all groups, the glomerular tufts did not express muscle actin using HHF 35, a specific immunolabel, suggesting that the proliferation in this model is not related to direct mesangial cell injury. This study shows that maneuvers that modulate the glomerular macrophage number are also associated with corresponding changes in the number of proliferating cells within the mesangium, suggesting a paracrine growth stimulation by the infiltrating macrophage during acute PA nephrosis. The infiltrating glomerular macrophage may be an effector mechanism for the propagation of initial glomerular injury to glomerulosclerosis by augmenting mesangial cell proliferation early in the course of this nonimmune progressive glomerulopathy.
Insights
Glomerular macrophages promote mesangial cell proliferation in puromycin aminonucleoside (PA) nephrosis. Modulating macrophage numbers altered proliferation, suggesting macrophages drive glomerulosclerosis progression via paracrine signaling.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Mesangial cell proliferation is a key feature of glomerulosclerosis in various kidney diseases.
- Glomerular macrophages infiltrate the kidney during acute puromycin aminonucleoside (PA) nephrosis, a model of nonimmune glomerulopathy.
- The interaction between macrophages and mesangial cells suggests a potential paracrine mechanism influencing mesangial cell growth.
Purpose of the Study:
- To investigate the role of glomerular macrophages in mesangial cell proliferation during acute PA nephrosis.
- To determine if modulating glomerular macrophage numbers affects mesangial cell proliferation.
- To explore the paracrine effect of macrophages on mesangial cell growth in this model.
Main Methods:
- Acute puromycin aminonucleoside (PA) nephrosis was induced in rats.
- Three maneuvers were used to alter glomerular macrophage numbers: essential fatty acid-deficient (EFAD) diet, cholesterol-supplemented diet (CSD), and X-irradiation (XI).
- Immunohistochemistry (ED-1 for macrophages, PCNA/cyclin for proliferation, BrdU for DNA synthesis) was employed to quantify cell populations and proliferation.
Main Results:
- An EFAD diet significantly reduced both glomerular macrophages and mesangial cell proliferation (r = 0.89, P < 0.05).
- A CSD significantly increased glomerular macrophages and mesangial cell proliferation (r = 0.95, P < 0.01).
- X-irradiation in CSD-fed PA rats decreased both macrophage and proliferation counts.
Conclusions:
- Modulating glomerular macrophage numbers directly correlates with changes in mesangial cell proliferation in PA nephrosis.
- Infiltrating glomerular macrophages appear to stimulate mesangial cell proliferation via paracrine mechanisms.
- Macrophages may act as effector cells propagating initial glomerular injury towards glomerulosclerosis by enhancing mesangial cell proliferation.