Role of connective tissue growth factor in experimental radiation nephropathy in rats.

BACKGROUND

Connective tissue growth factor (CTGF) is a potent fibrogenic cytokine which has been associated with progressive glomerulosclerosis and tubulointerstitial fibrosis. We investigated the role of CTGF on the progression of a rat model of radiation nephropathy.

METHODS

The model of radiation nephropathy in rats was established as follows: control group (n = 12), underwent only laparotomy; irradiated group (n = 20), underwent a laparotomy, then the rats were subjected to a single dose 25 Gy X-ray to the kidneys. The rats were followed up one, three, six and nine months after renal exposure to radiation.

RESULTS

Renal dysfunction was noted early in irradiated rats. Histological analysis showed focal glomerular sclerotic lesions at an early stage after irradiation. Radiation-induced glomerular and tubulointerstitial injuries were particularly severe the sixth month after irradiation as compared to the control group (P < 0.01). By immunohistochemistry, increased expression of CTGF was noted in the irradiated kidneys, which began to increase from the first month after irradiation, and remained significantly higher at the sixth and ninth month after irradiation (P < 0.01). Upon Western blot analysis CTGF protein expression showed an increase in the radiation treated kidneys compared with the control rats. The expression of CTGF closely correlated with the progression of radiation nephropathy. The expression of alpha-smooth muscle actin, vimentin, type III collagen and type IV collagen was also high in the irradiated kidney as compared to control rat kidneys (P < 0.05), and was most severe at the sixth and ninth month after irradiation (P < 0.01). By double immunostaining, CTGF expressing cells were found to be alpha-SMA-positive myofibroblasts and vimentin-positive tubular epithelial cells. Glomerular expression of CTGF closely correlated with the glomerular expression of alpha-SMA (r = 0.628, P < 0.01), vimentin (r = 0.462, P < 0.05) and accumulation of type IV collagen (r = 0.584, P < 0.01) in the irradiated kidney. Similarly, the expression of CTGF was positively correlated with the expression of alpha-SMA (r = 0.613, P < 0.01), vimentin (r = 0.629, P < 0.01), deposition of type III collagen (r = 0.741, P < 0.001) and type IV collagen (r = 0.799, P < 0.0001) in the tubulointerstitium of the irradiated kidney. Finally the expression of CTGF after the irradiation of the kidney positively correlated with the levels of blood urea nitrogen and serum creatinine.

CONCLUSION

Overexpression of CTGF may play an important role in the development and progression of glomerulosclerosis and tubulointerstitial fibrosis in radiation nephropathy.