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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Abstract
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.