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      Role of Apoptosis and Bcl-2/Bax in the Development of Tubulointerstitial Fibrosis during Experimental Obstructive Nephropathy


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          Background/Aims: To examine the role of apoptosis in experimental unilateral ureteral obstruction (UUO). Methods: Rat kidneys were examined 3, 7 and 11 days following UUO or sham operation (SO). Tissue was immunohistochemically stained for α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), Bcl-2 and Bax proteins. Apoptotic analysis was carried out in kidney sections using in situ end labelling of endonuclease cleaved DNA. Results: The relative volume (Vv) of cortical interstitium and interstitial α-SMA increased progressively following UUO. ED1-positive monocytes/macrophages peaked at day 7 and significantly decreased at day 11. PCNA-positive cells in tubulointerstitium were significantly increased on day 3. Staining returned to the level of the SO group by day 11, meanwhile those in the interstitium remained much higher than baseline. TUNEL-positive cells were persistently raised following UUO. Transient tubular cell proliferation seemed unable to counteract the apoptosis since tubular atrophy was apparently present by day 11 of UUO. However, interstitial cell proliferation was high enough to overwhelm apoptosis, particularly with respect ot myofibroblasts, since α-SMA immunostaining and Vv remained elevated. The ratio of the number of PCNA-positive cells to apoptotic cells formed a predictive pattern for the staining score of interstitial α-SMA (R<sup>2</sup> = 47.23%, p < 0.05) and Vv (R<sub>2</sub> = 49.93%, p < 0.05). Tubular Bcl-2 immunostaining peaked on day 3, and then gradually decreased to baseline by day 11. The expression of Bax protein was inhibited on day 3 when compared with that of the SO group, but increased with time following UUO. Conclusion: These findings suggest an important role for apoptosis and its regulatory proteins in the processes of tubular atrophy and fibrogenesis following UUO.

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          Most cited references3

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          Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

          Programmed cell death (PCD) plays a key role in developmental biology and in maintenance of the steady state in continuously renewing tissues. Currently, its existence is inferred mainly from gel electrophoresis of a pooled DNA extract as PCD was shown to be associated with DNA fragmentation. Based on this observation, we describe here the development of a method for the in situ visualization of PCD at the single-cell level, while preserving tissue architecture. Conventional histological sections, pretreated with protease, were nick end labeled with biotinylated poly dU, introduced by terminal deoxy- transferase, and then stained using avidin-conjugated peroxidase. The reaction is specific, only nuclei located at positions where PCD is expected are stained. The initial screening includes: small and large intestine, epidermis, lymphoid tissues, ovary, and other organs. A detailed analysis revealed that the process is initiated at the nuclear periphery, it is relatively short (1-3 h from initiation to cell elimination) and that PCD appears in tissues in clusters. The extent of tissue-PCD revealed by this method is considerably greater than apoptosis detected by nuclear morphology, and thus opens the way for a variety of studies.
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            The molecular biology of apoptosis.

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              Apoptosis and Expression of Bax Protein and Fas Antigen in Glomeruli of a Remnant-Kidney Model

              The role of apoptosis in glomerular cell depletion associated with a decrease in renal function is still controversial. To examine the involvement of apoptosis in renal disease, the occurrence of apoptosis during the progression of renal insufficiency as well as the expression of Bax protein and Fas antigen that are related to the apoptosis were investigated using five-sixths nephrectomized rats, one of the progressive renal disease models. Serum creatinine was significantly elevated to a level approximately five-fold higher than that in the sham-operated group on day 1 after the five-sixths nephrectomy and then maintained at a level approximately two- to three-fold higher until day 56 and then elevated further to a level eight-fold higher on day 96 after nephrectomy as compared with the sham-operated group. The total number of glomerular cells was significantly increased from day 7 to day 56 after nephrectomy and then returned to the level of the sham-operated group by day 96. The number of PCNA-positive cells (a marker of proliferating cells) in the glomeruli was significantly increased from day 7 to day 28 after nephrectomy; the highest level was observed on day 7, and the numbers then decreased gradually. Apoptotic cells, which were represented by TUNEL-positive cells, as well as apoptotic bodies were persistenly increased with time after nephrectomy in the glomeruli of nephrectomized rats; apoptotic cells could hardly be observed in the sham-operated group. Therefore, glomerular cell proliferation appeared to begin immediately after nephrectomy and to continue until day 28 at a level high enough to overcome the decrease in the number of glomerular cells due to apoptosis, since the total number of glomerular cells was apparently high until day 56. On day 96, the decrease in the number of glomerular cells probably becomes predominant over cell proliferation, since apoptosis continuously increased with time after nephrectomy. The events on day 96 may be associated with the severely decreased renal function which was represented by the explosive increase in the serum creatinine level on the same day. The number of Fas antigen positive glomerular cells was increased from day 1 after nephrectomy and reached a plateau on day 21. The number of Bax protein positive glomerular cells was generally increased with time after nephrectomy, but the number was slightly decreased on day 21. The theory that the expression of Bax protein is correlated with apoptosis appears to fit the case of progressive renal disease. These results suggest that apoptosis is involved in the cell depletion of progressive renal insufficiency.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2001
                11 January 2001
                : 9
                : 2
                : 71-80
                aSheffield Kidney Institute, Northern General Hospital, Sheffield, UK, and bNational Kidney Institute, 1st Affiliated Hospital, Sun Yat-sen University of Medical Science, Guangzhou, PR China
                52597 Exp Nephrol 2001;9:71–80
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 13, Tables: 2, References: 36, Pages: 10
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/52597
                Self URI (text/html): https://www.karger.com/Article/FullText/52597
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Apoptosis,Proliferation,Fibrosis,Tubulointerstitium,Myofibroblasts,Obstructive nephropathy,Bcl-2,Bax


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