Similar articles

Abstract: Astragalus mongholicus (AM) derived from the dry root of Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao is a widely used traditional Chinese medicine. The present study investigated the potential role of AM on renal fibrosis on a rat model of unilateral ureteral obstruction (UUO). We divided 48 Sprague-Dawley rats randomly into 4 groups: sham-operated group (Sham), untreated UUO group, AM-treated (10 g/(kg∙d)) UUO group, and losartan-treated (20 mg/(kg∙d)) UUO group as positive control. Haematoxylin & eosin (HE) and Masson staining were used to study the dynamic histological changes of the kidneys 7 and 14 d after operation. The expressions of fibronectin (FN), type I collagen (colI), hepatocyte growth factor (HGF), transforming growth factor-&beta;1 (TGF-&beta;1), and α-smooth muscle actin (α-SMA) were analyzed by real-time polymerase chain reaction (PCR), immunohistochemistry staining, and Western blot. Results show that, similar to losartan, AM alleviated the renal damage and decreased the deposition of FN and colI from UUO by reducing the expressions of TGF-β1 and α-SMA (P<0.05), whereas HGF increased greatly with AM treatment (P<0.05). Our findings reveal that AM could retard the progression of renal fibrosis. The renoprotective effect of AM might be related to inhibition of myofibroblast activation, inducing of HGF and reducing of TGF-β1 expression.

[1] Blobe, G.C., Schiemann, W.P., Lodish, H.F., 2000. Role of transforming growth factor beta in human disease. N. Engl. J. Med., 342(18):1350-1358.

[2] Bowes, R.C.3rd, Lightfoot, R.T., van de Water, B., Stevens, J.L., 1999. Hepatocyte growth factor induces tubulogenesis of primary renal proximal tubular epithelial cells. J. Cell. Physiol., 180(1):81-90.

[3] Chevalier, R.L., 1999. Molecular and cellular pathophysiology of obstructive nephropathy. Pediatr. Nephrol., 13(7): 612-619.

[4] Chevalier, R.L., Goyal, S., Kim, A., Chang, A.Y., Landau, D., LeRoith, D., 2000. Renal tubulointerstitial injury from ureteral obstruction in the neonatal rat is attenuated by IGF-1. Kidney Int., 57(3):882-890.

[5] Dai, C., Yang, J., Bastacky, S., Xia, J., Li, Y., Liu, Y., 2004. Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J. Am. Soc. Nephrol., 15(10):2637-2647.

[6] Eddy, A.A., 1996. Molecular insithts into renal interstitial fibrosis. J. Am. Soc. Nephrol., 7(12):2495-2508.

[7] Esposito, C., Parrilla, B., de Mauri, A., Cornacchia, F., Fasoli, G., Foschi, A., Mazzullo, T., Plati, A., Scudellaro, R., Dal Canton, A., 2005. Hepatocyte growth factor (HGF) modulates matrix turnover in human glomeruli. Kidney Int., 67(6):2143-2150.

[8] Essawy, M., Soylemezoglu, O., Muchaneta-Kubara, E.C., Shortland, J., Brown, C.B., el Nahas, A.M., 1997. Myofibroblasts and the progression of diabetic nephropathy. Nephrol. Dial. Transplant., 12(1):43-50.

[9] Fan, J.M., Ng, Y.Y., Hill, P.A., Nikolic-Paterson, D.J., Mu, W., Atkins, R.C., Lan, H.Y., 1999. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int., 56(4): 1455-1467.

[10] Fu, P., Liu, F., Su, S., Wang, W., Huang, X.R., Entman, M.L., Schwartz, R.J., Wei, L., Lan, H.Y., 2006. Signaling mechanism of renal fibrosis in unilateral ureteral obstructive kidney disease in ROCK1 knockout mice. J. Am. Soc. Nephrol., 17(11):3105-3114.

[11] Gong, R., Rifai, A., Tolbert, E.M., Centracchio, J.N., Dworkin, L.D., 2003. Hepatocyte growth factor modulates matrix metalloproteinases and plasminogen activator/plasmin proteolytic pathways in progressive renal interstitial fibrosis. J. Am. Soc. Nephrol., 14(12):3047-3060.

[12] Gross, O., Schulze-Lohoff, E., Koepke, M.L., Beirowski, B., Addicks, K., Bloch, W., Smyth, N., Weber, M., 2004. Antifibrotic, nephroprotective potential of ACE inhibitor vs AT1 antagonist in a murine model of renal fibrosis. Nephrol. Dial. Transplant., 19(7):1716-1723.

[13] Han, X., Wang, J.J., Fan, S.K., 2000. Study on pharmacology of Astragalus injection. Beijing Zhong Yi, 19(1):44-45 (in Chinese).

[14] Iwano, M., Neilson, E.G., 2004. Mechanisms of tubulointerstitial fibrosis. Curr. Opin. Nephrol. Hypertens., 13(3):279-284.

[15] Iwano, M., Plieth, D., Danoff, T.M., Xue, C., Okada, H., Neilson, E.G., 2002. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest., 110(3):341-350.

[16] Klahr, S., Morrissey, J., 2002. Obstructive nephropathy and renal fibrosis. Am. J. Physiol. Renal Physiol., 283(5): F861-F875.

[17] Liu, Y., 1999. Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am. J. Physiol., 277(4 Pt 2):F624-F633.

[18] Liu, Y., 2004a. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J. Am. Soc. Nephrol., 15(1):1-12.

[19] Liu, Y., 2004b. Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action. Am. J. Physiol. Renal Physiol., 287(1):F7-F16.

[20] Liu, Y., Yang, J., 2006. Hepatocyte growth factor: new arsenal in the fights against renal fibrosis? Kidney Int., 70(2): 238-240.

[21] Mizuguchi, Y., Miyajima, A., Kosaka, T., Asano, T., Asano, T., Hayakawa, M., 2004. Atorvastatin ameliorates renal tissue damage in unilateral ureteral obstruction. J. Urol., 172(6):2456-2459.

[22] Mizuno, S., Matsumoto, K., Kurosawa, T., Mizuno-Horikawa, Y., Nakamura, T., 2000. Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta 1 in renal fibrosis in mice. Kidney Int., 57(3):937-948.

[23] Mizuno, S., Matsumoto, K., Nakamura, T., 2001. Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int., 59(4): 1304-1314.

[24] Moon, J.A., Kim, H.T., Cho, I.S., Sheen, Y.Y., Kim, D.K., 2006. IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int., 70(7): 1234-1243.

[25] Mou, S., Zhang, Q.Y., Ni, Z.H., Tong, J.F., 2002. Effect of Astragalus membranaceus on HGF by renal interstitial fibroblasts in the high glucose. Zhong Guo Zhong Xi Yi Jie He Shen Bing Za Zhi, 3(1):7-9 (in Chinese).

[26] Nakao, N., Yoshimura, A., Morita, H., Takada, M., Kayano, T., Ideura, T., 2003. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet, 361(9352):117-124.

[27] Nowak, G., Schnellmann, R.G., 1996. Autocrine production and TGF-beta 1-mediated effects on metabolism and viability in renal cells. Am. J. Physiol., 271(3 Pt 2): F689-F697.

[28] Peters, H., Border, W.A., Noble, N.A., 1998. Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade. Kidney Int., 54(5):1570-1580.

[29] Pfaffl, M.W., Horgan, G.W., Dempfle, L., 2002. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res., 30(9):e36.

[30] Remuzzi, G., Bertani, T., 1998. Pathophysiology of progressive nephropathies. N. Engl. J. Med., 339(20): 1448-1456.

[31] Roberts, I.S., Burrows, C., Shanks, J.H., Venning, M., McWilliam, L.J., 1997. Interstitial myofibroblasts: predictors of progression in membranous nephropathy. J. Clin. Pathol., 50(2):123-127.

[32] Strutz, F., Zeisberg, M., Ziyadeh, F.N., Yang, C.Q., Kalluri, R., Müller, G.A., Neilson, E.G., 2002. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int., 61(5):1714-1728.

[33] Taal, M.W., Brenner, B.M., 2000. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int., 57(5):1803-1817.

[34] Taal, M.W., Zandi-Nejad, K., Weening, B., Shahsafaei, A., Kato, S., Lee, K.W., Ziai, F., Jiang, T., Brenner, B.M., MacKenzie, H.S., 2000. Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney. Kidney Int., 58(4):1664-1676.

[35] Taipale, J., Keski-Oja, J., 1996. Hepatocyte growth factor releases epithelial and endothelial cells from growth arrest induced by transforming growth factor-β1. J. Biol. Chem., 271(8):4342-4348.

[36] Taipale, J., Saharinen, J., Hedman, K., Keski-Oja, J., 1996. Latent transforming growth factor-beta 1 and its binding protein are components of extracellular matrix microfibrils. J. Histochem. Cytochem., 44(8):875-889.

[37] Wen, J.G., Frøkiaer, J., Jørgensen, T.M., Djurhuus, J.C., 1999. Obstructive nephropathy: an update of the experimental research. Urol. Res., 27(1):29-39.

[38] Xie, X., Yang, M., Liu, H., Zuo, C., Li, Z., Deng, Y., Fan, J., 2008. Influence of ginsenoside Rg1, a panaxatriol saponin from Panax notoginseng, on renal fibrosis in rats with unilateral ureteral obstruction. J. Zhejiang Univ. Sci. B, 9(11):885-894.

[39] Xue, H., Fan, J.M., Chen, L., Li, Z., Hu, Z.X., Liu, X.R., 2005. Identification and characterization of hepatocyte growth factor in counteracting tubular epithelial-myofibroblast transdifferentiation in renal interstitial fibrosis. Zhong Hua Shen Zang Bing Za Zhi, 21(8):458-463 (in Chinese).

[40] Yang, H.X., Zhu, M.Y., 2005. Renoprotective effect of Astragalus membranaceus on rats with diabetic nephropathy. Shi Yong Yi Xue Za Zhi, 21(17):1964-1965 (in Chinese).

[41] Yang, J., Liu, Y., 2002. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J. Am. Soc. Nephrol., 13(1):96-107.

[42] Yang, J., Shultz, R.W., Mars, W.M., Rodney, E.W., Li, Y., Dai, C., Kari, N., Liu, Y., 2002. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J. Clin. Invest., 110(10):1525-1538.

[43] Yang, J., Dai, C., Liu, Y., 2005. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. J. Am. Soc. Nephrol., 16(1): 68-78.

[44] Zhong, H., Fan, J.M., Li, Z., Liu, F., Yang, L.C., Ji, L., Sha, Z.H., Ma, X.Y., 2005. Effects of hepatocyte growth factor on TGF-beta1 triggered tubular epithelial-myofibroblast transdifferentiation by CTGF in vitro. Sichuan Da Xue Xue Bao Yi Xue Ban, 36(5):653-656, 691 (in Chinese).