Glomerular macrophages and the mesangial proliferative response in the experimental nephrotic syndrome.
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.
Diamond
J R
JR
Department of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033.
Ding
G
G
Frye
J
J
Diamond
I P
IP
D000818:Animals; D002455:Cell Division; D002791:Cholesterol, Dietary; D005228:Fatty Acids, Essential / Q000172:deficiency; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology*; D008055:Lipids / Q000502:physiology*; D008264:Macrophages / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000473:pathology*; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley; D014916:Whole-Body Irradiation
D002791:Cholesterol, Dietary; D005228:Fatty Acids, Essential; D008055:Lipids; D011692:Puromycin Aminonucleoside