Apoptosis in progressive crescentic glomerulonephritis.
Recent studies in the experimental proliferative glomerulonephritis (GN) indicate that apoptosis is the major mechanism that mediates the resolution of glomerular hypercellularity during the repair process of experimental GN. The role of apoptosis during progressive GN, however, has not yet been well understood. We have, therefore, examined the role of apoptosis during the progression of experimental crescentic GN to end-stage renal failure. A progressive model of antiglomerular basement membrane GN was induced in Wistar-Kyoto rats with a single injection of anti-rat glomerular basement membrane antibody. Renal function and histologic studies were performed chronologically from Day 0 to Week 8 after disease induction. The incidence of apoptosis in glomeruli as well as glomerular crescents was examined during the progression of crescentic GN to end-stage kidney disease. Many leukocytes infiltrated glomeruli from the early phase of GN, and severe necrotizing and mesangiolytic glomerular damage was observed from Day 5 to Week 3. After glomerular damage, mesangial hypercellularity with mesangial cell proliferation and extracellular matrix accumulation began with crescent formation. Thereafter, glomerular inflammation continued with marked extracellular matrix accumulation until Week 4, and the renal function deteriorated. The proliferative glomerular lesions subsequently progressed to sclerotic lesions and eventually to chronic renal failure in Week 8. Although the number of proliferating cells and infiltrating leukocytes slowly decreased, glomerular inflammation resolved with scar formation as mesangial sclerosis. Significant apoptosis was present from Day 7 (mean +/- SEM, 0.53 +/- 0.12 cells/glomerular cross-section) and gradually increased in number with the proliferating lesions as glomerular inflammation continued. Moreover, apoptosis increased during the resolution of the glomerular inflammation, and many apoptotic cells were present in the sclerotic lesions in Week 8 (1.97 +/- 0.27 cells/glomerular cross-section). As glomerular inflammation subsided, cellular crescents progressed to fibrous crescents with a reduction of cellularity by Week 8, and apoptosis increased significantly within these lesions. These findings indicate that apoptosis plays an essential role in the resolution of intra- and extraglomerular inflammation and in the elimination of glomerular cells within the scarring regions for progressive crescentic GN. The regulation of the apoptotic phenomenon during crescentic GN may be important in the progression of glomerular inflammation and the development of pathologic glomerular sclerosis.
Shimizu
A
A
Department of Pathology, Nippon Medical School, Tokyo, Japan.
Masuda
Y
Y
Kitamura
H
H
Ishizaki
M
M
Sugisaki
Y
Y
Yamanaka
N
N
D000818:Animals; D017209:Apoptosis; D001485:Basement Membrane / Q000276:immunology; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000473:pathology; D005920:Glomerular Mesangium / Q000473:pathology; D005921:Glomerulonephritis / Q000473:pathology*; D007678:Kidney Glomerulus / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D008854:Microscopy, Electron; D009336:Necrosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011921:Rats, Inbred WKY; D012598:Sclerosis / Q000473:pathology
D018809:Proliferating Cell Nuclear Antigen; D004247:DNA; D017493:Leukocyte Common Antigens