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      Apoptotic Cell Loss following Cell Proliferation in Renal Glomeruli of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Type 2 Diabetes

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          Background: The mechanism of glomerular cell loss during the late stage of diabetic nephropathy is unknown. Methods: We examined cell population, proliferation, apoptosis, and immunohistochemical expression of apoptosis-related proteins, Bcl-2 and Bax, in renal glomeruli of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of human type 2 diabetes. 10-, 30-, 50-, and 70-week-old rats were used (n = 5–8). Control was the Long-Evans Tokushima Otsuka (LETO) rat. Results: The cell population in renal glomeruli of OLETF rats progressively increased with age, but decreased at 70 weeks old. High cell proliferative activity based on proliferating cell nuclear antigen (PCNA) expression was limited during the early stage, whereas by in situ nick end-labeling (TUNEL), Taq polymerase based in situ ligation, and electron microscopy, apoptosis was detected during the late stage (50 and 70 weeks old). Augmented expression of Bax, but not of Bcl-2, was evident in glomeruli of OLETF rats during the late stage, which contributed to an increased Bax/Bcl-2 ratio. Conclusion: It appears that high cell proliferative activity and the subsequent cell loss via apoptosis counterbalance each other and determine glomerular cell population of OLETF rats. Augmented Bax expression may be one of the important regulators of this apoptosis.

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          Most cited references 4

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          Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death

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            Structure-Function Analysis of Bcl-2 Protein

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              Glucose loading induces DNA fragmentation in rat proximal tubular cells.

               K Numakami,  H Itoh,  T Saruta (1996)
              A 10% glucose, 10% mannitol, or 0.9% saline solution was infused in male Wistar rats for 300 minutes via the left cervical vein. Glomerular filtration rates (GFRs) were not significantly altered in any of the three groups. DNA was extracted from isolated proximal tubular cells at the end of each infusion. Electrophoresis on agarose gels showed a distinct ladder pattern of DNA fragmentation in 10% glucose-loaded rats, but no such pattern in 10% mannitol- or 0.9% saline-loaded rats. After infusion for 300 minutes, the plasma glucose level of the 10% glucose-loaded group was higher than that of the other two groups (each P < .005). These results suggest that hyperglycemia led to DNA fragmentation in the DNA of proximal tubular cells, similar to the process of programmed cell death known as apoptosis. DNA fragmentation may be associated with renal proximal tubular damage in the early stages of diabetic nephropathy.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                December 2002
                07 October 2002
                : 22
                : 5-6
                : 587-595
                aSecond Department of Internal Medicine, Gifu University School of Medicine, Gifu, and bDepartment of Food Science, Kyoto Women’s University, Kyoto, Japan
                65284 Am J Nephrol 2002;22:587–595
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 6, Tables: 1, References: 26, Pages: 9
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65284
                Laboratory Investigation

                Cardiovascular Medicine, Nephrology

                Apoptosis, Diabetes mellitus, Diabetic nephropathy, Glomerulus


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