- Apoptosis and Cell Proliferation in Experimental Acute Tubular Necrosis Induced by Intramuscular Glycerol Injection.
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Wan Seop Kim, Jung Woo Noh, Moon Hyang Park
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Korean J Pathol. 2003;37(1):41-49.
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 Abstract
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- BACKGROUND
Acute tubular necrosis (ATN) is the most common cause of acute renal failure. It is characterized by the destruction of tubular epithelial cells. To examine apoptosis and proliferative activity of tubular cells in the course of acute tubular necrosis, we induced acute renal failure by intramuscular hypertonic glycerol injection to New Zealand White rabbits.
METHODS
The immunohistochemistry was done for Ki-67 and tissue-transglutaminase (tTG), and the terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) method was performed using a total of 77 renal specimens including 29 gun biopsies and 48 nephrectomiy specimens.
RESULTS
Widespread tubular injury with pigment casts and interstitial hemorrhage were noted. The tubular proliferation index was increased at 2 hours after glycerol injection, and the index peaked at 3 hours. The second cell proliferation peak was noted at 3 days. Apoptotic cells were identified by TUNEL and tTG staining. The apoptotic index was significantly increased, and it peaked at 24 hours after glycerol injection. There was a significant correlation between the proliferation index (MIB-1) the and the apototic index (TUNEL)(p= 0.001). A DNA ladder pattern was observed at 6 to 8 hours.
CONCLUSIONS
Tubular cell proliferation and apoptosis occur in the early phase after the induction of acute tubular necrosis, and the excess hyperplastic epithelial cells appear to be eliminated by apoptosis.
- Apoptosis in Renal Hypertrophy after Uninephrectomy in the Rats.
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Chan Pil Park, Jung Woo Noh, Joo Seob keum, Myung Sook Kim, Moon Hyang Park
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Korean J Pathol. 2001;35(6):513-523.
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Abstract
- BACKGROUND
Glomerular compensatory hypertrophy maintains decreased renal function after uninephrectomy (UNX).
Proliferation and apoptosis of renal cells may be involved in hypertrophy.
METHODS
In small and large male Sprague-Dawley rats, contralateral kidneys were harvested 1, 7, 14 and 30 days after UNX. Apoptosis was assessed by the Tdt-mediated dUTP-digoxigenin nick end labelling method. Proliferating cell nuclear antigen and Fas ligand (FasL) expression was determined by immunohistochemically.
RESULTS
Morphometrically, glomerular hypertrophy was observed in both small and large rats after UNX, and it was more significant in the small rats. The glomerular proliferation index (PI) was gradually increased from day 7 but decreased on day 30 in the small rats. Glomerular PI was significantly increased from day 7 in large rats and peaked at day 14. Apoptotic cells in the glomeruli were slightly increased on day 1 and on day 7 in both groups of rats. The expression of FasL was gradually increased in the distal tubular epithelium in both groups.
CONCLUSIONS
These results demonstrate different profiles regarding the compensatory growth of the kidney, cell proliferation, and apoptosis during the period of compensatory hypertrophy in uninephrectomized rats of different weight and age. Apoptosis may play a role in regressing a number of proliferated cells during renal compensatory hypertrophy.
- The Role of MIB-1 Expression and Apoptosis in Experimental Crescentic Glomerulonephritis.
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Nam Hoon Kim, Wan Seop Kim, Jung Woo Noh, Moon Hyang Park
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Korean J Pathol. 1999;33(4):231-242.
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Abstract
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- It has been postulated that programmed cell death via apoptosis may be critical for remodelling of glomeruli after inflammatory injury. To understand the regulatory mechanism of apoptosis in experimental crescentic glomerulonephritis (CGN), we examined the MIB-1 score (proliferation index, PI) and apoptotic index during the progression of experimental CGN to end-stage renal failure. CGN was induced in New Zealand White rabbits by administration of guinea pig anti-GBM IgG after sensitization with guinea pig IgG and their kidneys were analyzed for the development of crescents through sequential renal biopsies. Serum creatinine levels progressively increased in a time course until day 45. The PI in glomeruli, tubular epithelial cells, and interstitium progressively increased during the progression of experimental CGN. The mean numbers of MIB-1 positive intraglomerular nuclei (PI) were significantly correlated with degrees of crescent formation and the numbers of apoptotic cells in the glomeruli, tubules, and interstitium.
Significant apoptosis was present from day 1 (15.8 10.16 cells/glomerular cross section) and increased in number with the proliferative 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 day 17 (18.6 12.99 cells/glomerular cross section). As glomerular inflammation subsided, cellular crescents progressed to fibrous crescents with a reduction of cellularity by day 45. On day 45, the glomerular PI and the numbers of apoptotic cells were markedly decreased. The correlations found in CGN between the creatinine level and the percentage of crescents, between the percentage of crescent and PI, and between the PI and number of apoptotic cells support the hypothesis that there is a change in the glomerular and tubulo-interstitial apoptosis under pathologic conditions. 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 sclerotic regions for progressive CGN. The regulation of the apoptotic phenomenon and increased PI during CGN may be important in the progression of glomerular inflammation and the development of pathologic glomerular sclerosis.
- Sequential Changes of Extracellular Matrix mRNA in Anti-GBM Antibody Induced Crescentic Glomerulonephritis in the Rabbit.
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Moon Hyang Park, Unn Wha Lee, In Sup Han, Rho Won Chun, Jung Woo Noh
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Korean J Pathol. 1998;32(9):627-637.
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Abstract
- Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency, however, the mechanism regarding renal fibrosis in renal injury is not well understood. Recently, several kinds of cytokines have been known to be related to fibrosis after renal injury. The interaction between elements regulating fibrogenesis would be better understood by looking at the effect of TGF-beta1 on the synthesis and accumulation of extracellular matrix, especially collagenous proteins.
Crescentic glomerulonephritis (CGN) was induced in New Zealand White rabbits by administration of guinea pig anti-GBM IgG after sensitization with guinea pig IgG; and their kidneys were analyzed for the development of crescents and fibrosis through sequential renal biopsies. Serum creatinine levels in a time course progressively increased until day 15. We semi-quantitatively assayed the levels of the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA factored for GAPDH mRNA using RT-PCR. We observed a progressive interstitial fibrosis and the expression of collagen I both in the cortex and medulla. The effect of repeated renal biopsy itself on pathology and on the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA in a time course were not significant, but a very mild increase of the expression of alpha1(I) collagen mRNA was noted at day 15. Histology showed a progressive crescent formation and interstitial fibrosis in a time course that roughly paralleled the expression of alpha1(I) collagen mRNA in both cortex and medulla. TGF-beta1 mRNA was hardly expressed at day 0 in cortex as well as in medulla. It was elevated from day 1, peaked at day 7, and then decreased. In medulla, TGF-beta1 mRNA was noticeably expressed at day 1, peaked at day 4, and then decreased. The expression of alpha1(I) collagen mRNA was seen even before inducing CGN. It was gradually and continuously increased until day 15 both in cortex and medulla. These results suggest that the expression of TGF-beta1 mRNA precedes that of alpha1(I) collagen mRNA in the early stage of CGN and has a central role for provoking the accumulation the collagen I, the most representative interstitial extracellular matrix, in the rabbit model CGN induced by anti-GBM antibody. We conclude that the measurement of the expression of TGF-beta1 mRNA and/or alpha1(I) collagen mRNA in a biopsy sample can be a useful predictor for renal outcome.
- Sequential Studies of Glomerular Crescent Formation in Rabbits with Anti-Glomerular Basement Membrane(GBM) Antibody Induced Glomerulonephritis(GN).
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Hye Seon Ahn, Jung Woo Noh, Moon Hyang Park
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Korean J Pathol. 1997;31(3):219-232.
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Abstract
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- To investigate the mechanism of crescent formation, sequential pathologic changes from the New Zealand White rabbits with anti-GBM antibody induced GN by administration of guinea pig anti-GBM IgG were studied by light (LM), immunofluorescent (IF) and electron (EM) microscopy.
Although no glomerular changes were observed in LM, swelling of the endothelial cells and the epithelial cells were noted in EM by day 2. By day 7, early and cellular crescents were evident. Proteinaceous materials and fibrins were noted in the glomerular capillary lumina (GCL) and Bowman's space (BS) associated with segmental hypercellularity. The GBM damage became progressively severe, followed by focal detachment of the visceral epithelial cells from the GBM. At day 14, fibrin strands, mononuclear cells and collagen fibrils were present between the proliferating extracapillary cells. At day 31, fibrocellular crescents were predominated. Elongated spindle cells, morphologically resembling myofibroblasts, were noted near the Bowman's capsule (BC). A degree of tubular atrophy, interstitial fibrosis, and inflammatory infiltrates increased as it did with fibrous organization of crescent. Intense linear IF staining for IgG and C3 were seen throughout the experiments along the GBM. In conclusion, the progression of crescent from an early "proteinaceous" stage through cellular, fibrocellular and fibrous stages was well documented in this study. Inflammatory cells and coagulation mechanism may activate the initiation of the GBM damage at the early stage. Activated periglomerular mononuclear cells may also cause disruption of BC which facilitates entry of activated periglomerular cells and fibroblasts into BS leading to progressive fibrous crescent formation.
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