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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.

Background: Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy. Methods: Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks. Results: The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 ± 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 ± 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-β1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice. Conclusions: The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.

These data suggest that apoptosis is involved in the advancement of diabetic nephropathy, and that plasma sFas level might be a predicting factor for prognosis.

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