APOPTOSIS IN PROGRESSIVE CRESCENTIC GLOMERULONEPHRITIS

Recent studies in the experimental proliferative glomerulonephritis (G N) indicate that apoptosis is the major mechanism that mediates the re solution of glomerular hypercellularity during the repair process of e xperimental GN. The role of apoptosis during progressive GN, however, has not yet been well understood. We have, therefore, examined the rol e of apoptosis during the progression of experimental crescentic GN to end-stage renal failure. A progressive model of antiglomerular baseme nt membrane GN was induced in Wistar-Kyoto rats with a single injectio n of anti-rat glomerular basement membrane antibody. Renal function an d 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 c rescentic GN to end-stage kidney disease. Many leukocytes infiltrated glomeruli from the early phase of GN, and severe necrotizing and mesan giolytic glomerular damage was observed from Day 5 to Week 3. After gl omerular damage, mesangial hypercellularity with mesangial cell prolif eration and extracellular matrix accumulation began with crescent form ation. Thereafter, glomerular inflammation continued with marked extra cellular matrix accumulation until Week 4, and the renal function dete riorated. 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 leukocy tes slowly decreased, glomerular inflammation resolved with scar forma tion as mesangial sclerosis. Significant apoptosis was present from Da y 7 (mean +/- SEM, 0.53 +/- 0.12 cells/glomerular cross-section) and g radually increased in number within the proliferating lesions as glome rular inflammation continued. Moreover, apoptosis increased during the resolution of the glomerular inflammation, and many apoptotic cells w ere present in the sclerotic lesions in Week 8 (1.97 +/- 0.27 cells/gl omerular cross-section). As glomerular inflammation subsided, cellular crescents progressed to fibrous crescents with a reduction of cellula rity by Week 8, and apoptosis increased significantly within these les ions. These findings indicate that apoptosis plays an essential role i n the resolution of intra- and extraglomerular inflammation and in the elimination of glomerular cells within the scarring regions for progr essive crescentic GN. The regulation of the apoptotic phenomenon durin g crescentic GN may be important in the progression of glomerular infl ammation and the development of pathologic glomerular sclerosis.