Role of Connective Tissue Growth Factor and Angiotensin II in Tubulointerstitial Fibrosis in Experimental Obstructive Nephropathy
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概要
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Angiotensin II (Ang-II) and connective tissue growth factor (CTGF) are involved in various renal disorders that lead to end-stage renal disease. Here, we determined the role of Ang-II and CTGF in the progression of tubulointerstitial injury in the rat unilateral ureteral obstruction (UUO) model. Sprague-Dawley rats (n=16) were used; 10 rats underwent UUO, and 6 control rats underwent sham operation; and rats of both groups were sacrificed on days 7 or 14. Histomorphometric analysis was performed to quantitate tubulointerstitial injuries in the experimental group. Kidney sections were stained immunohistochemically for Ang-II, CTGF, transforming growth factor-β1 (TGF-β1), type III collagen and α-smooth muscle actin (α-SMA). Renal CTGF expression was studied using <I>in situ</I> hybridization and reverse transcriptase-polymerase chain reaction. Double staining for Ang-II with α-SMA and CTGF with α-SMA was performed to identify cells with enhanced expression of Ang-II and CTGF. Similar dual staining of Ang-II with type III collagen and CTGF with type III collagen was performed. The correlation between Ang-II and CTGF expression and tubulointerstitial injury was examined. In obstructed kidneys, there was a significant (<I>p</I><0.001) increase in expression of Ang-II, CTGF, TGF-β1, type III collagen and α-SMA, compared with control kidneys. Tubular epithelial cells and interstitial cells were the main Ang-II- and CTGF-producing cells in the obstructed kidneys. A significantly (<I>p</I><0.001) positive correlation was detected in obstructed kidneys between renal expression of CTGF and expression of TGF-β1 (<I>r</I>=0.91), type III collagen (<I>r</I>=0.87) or α-SMA (<I>r</I>=0.90). Similarly a significantly (<I>p</I><0.001) positive correlation was found in obstructed kidneys between Ang-II expression and expression of TGF-β1 (<I>r</I>=0.88), type III collagen (<I>r</I>=0.79) and α-SMA (<I>r</I>=0.91). Finally, there were significantly positive correlations between CTGF /Ang-II expression and tubulointerstitial fibrosis in the obstructed kidneys (<I>r</I>=0.88, <I>p</I><0.001). The results of our <I>in vivo</I> studies suggest that both Ang-II and CTGF, produced by intrarenal cells, coordinately regulate progression of renal tubulointerstitial injury, by facilitating increased accumulation of interstitial collagens in obstructed kidneys.
- 長崎大学医学部の論文
長崎大学医学部 | 論文
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