RhoA特异性RNA干扰对HSC-T6细胞外基质表达的影响
|
摘要
目的:探讨针对大鼠RhoA基因的RNA干扰技术对HSC-T6 RhoA、Ⅰ型胶原(CollagenⅠ,ColⅠ)、Ⅲ型前胶原(Procollagen typeⅢ,PCⅢ)、透明质酸(Hyaluronic acid ,HA)及层粘连蛋白(Laminin,LN)的影响。
方法:将阴性质粒(HK-A质粒)及大鼠RhoA基因特异性siRNA表达质粒(Rat1质粒、Rat2质粒)转染至大鼠肝星状细胞HSC-T6。将细胞分组如下:A组(正常培养)、B组(转染HK-A质粒)、C组(转染Rat1质粒)、D组(转染Rat2质粒)。用RT-PCR技术检测细胞RhoA、ColⅠ、PCⅢmRNA的表达。用ELISA方法检测培养上清中HA及LN的含量。
结果:Rat1质粒所介导的RNAi技术能有效抑制大鼠肝星状细胞HSC-T6 RhoA、PCⅢ、ColⅠmRNA表达量及培养上清中HA及LN生成量。与A组相比,C组RhoA、PCⅢmRNA表达量下降(p﹤0.05),ColⅠmRNA、HA及LN表达量也显著下降(p﹤0.01),五者抑制率分别为43.77%、43.68%、71.00%、59.53%、93.08%。而B组、D组与A组相比,表达量均无统计学差异(p﹥0.05)。
结论:以RhoA为干预点,Rat1质粒所介导的RNAi技术能有效抑制大鼠肝星状细胞HSC-T6细胞外基质的生成,为体内的进一步研究提供了实验基础。
OBJECTIVE: To investigate the effect of RNA interference targeting RhoA gene on the expression of RhoA, Collagen typeⅠ(ColⅠ), Prollagen typeⅢ(PCⅢ), hyaluronic acid(HA)and laminin(LN)in rat hepatic stellate cell HSC-T6.
METHODS: Transfect negative control plasmid vectors (named HK-A) and rat RhoA gene specific siRNA expressing plasmid vectors(named Rat1 and Rat2)into rat hepatic stellate cell HSC-T6 respectively. Divide the HSC-T6 cells into four groups as following: group A (cultured normally)、group B (transfected with HK-A)、group C (transfected with Rat1)、group D (transfected with Rat2). The mRNA expression of RhoA, ColⅠand PCIII in HSC-T6 was detected by reverse-transcription polymerase chain reaction(RT-PCR)respectively in each group. The content of HA and LN in culture serum was measured by specific enzyme-linked immunosorbent assay (ELISA).
RESULTS: Compared with group A, the expression of RhoA, ColⅠ, PCIII, HA and LN were decreased in group C (p﹤0.05 for RhoA and PCIII, the inhibition ratios were 43.77% and 43.68%. p﹤0.01 for ColⅠ, HA and LN , the inhibition ratios were 71.00%, 59.53% and 93.08% respectively). Otherwise, compared with group A, there was no significant difference in group B or group D for the five indexs (p﹥0.05).
CONCLUSION: RNA interference mediated by Rat1 plasmids targeting RhoA can depress the expression of ColⅠ, PCⅢ, HA and LN in rat hepatic stellate cell HSC-T6, which has provided experimental foundation for further research in vivo.
方法:将阴性质粒(HK-A质粒)及大鼠RhoA基因特异性siRNA表达质粒(Rat1质粒、Rat2质粒)转染至大鼠肝星状细胞HSC-T6。将细胞分组如下:A组(正常培养)、B组(转染HK-A质粒)、C组(转染Rat1质粒)、D组(转染Rat2质粒)。用RT-PCR技术检测细胞RhoA、ColⅠ、PCⅢmRNA的表达。用ELISA方法检测培养上清中HA及LN的含量。
结果:Rat1质粒所介导的RNAi技术能有效抑制大鼠肝星状细胞HSC-T6 RhoA、PCⅢ、ColⅠmRNA表达量及培养上清中HA及LN生成量。与A组相比,C组RhoA、PCⅢmRNA表达量下降(p﹤0.05),ColⅠmRNA、HA及LN表达量也显著下降(p﹤0.01),五者抑制率分别为43.77%、43.68%、71.00%、59.53%、93.08%。而B组、D组与A组相比,表达量均无统计学差异(p﹥0.05)。
结论:以RhoA为干预点,Rat1质粒所介导的RNAi技术能有效抑制大鼠肝星状细胞HSC-T6细胞外基质的生成,为体内的进一步研究提供了实验基础。
OBJECTIVE: To investigate the effect of RNA interference targeting RhoA gene on the expression of RhoA, Collagen typeⅠ(ColⅠ), Prollagen typeⅢ(PCⅢ), hyaluronic acid(HA)and laminin(LN)in rat hepatic stellate cell HSC-T6.
METHODS: Transfect negative control plasmid vectors (named HK-A) and rat RhoA gene specific siRNA expressing plasmid vectors(named Rat1 and Rat2)into rat hepatic stellate cell HSC-T6 respectively. Divide the HSC-T6 cells into four groups as following: group A (cultured normally)、group B (transfected with HK-A)、group C (transfected with Rat1)、group D (transfected with Rat2). The mRNA expression of RhoA, ColⅠand PCIII in HSC-T6 was detected by reverse-transcription polymerase chain reaction(RT-PCR)respectively in each group. The content of HA and LN in culture serum was measured by specific enzyme-linked immunosorbent assay (ELISA).
RESULTS: Compared with group A, the expression of RhoA, ColⅠ, PCIII, HA and LN were decreased in group C (p﹤0.05 for RhoA and PCIII, the inhibition ratios were 43.77% and 43.68%. p﹤0.01 for ColⅠ, HA and LN , the inhibition ratios were 71.00%, 59.53% and 93.08% respectively). Otherwise, compared with group A, there was no significant difference in group B or group D for the five indexs (p﹥0.05).
CONCLUSION: RNA interference mediated by Rat1 plasmids targeting RhoA can depress the expression of ColⅠ, PCⅢ, HA and LN in rat hepatic stellate cell HSC-T6, which has provided experimental foundation for further research in vivo.
引文
1. Pinzani M, Marra F, Carloni V.Signal transduction in hepatic stellate cells. Liver. 1998 Feb;18(1):2-13.
2. Shimizu Y, Dobashi K, Iizuka K, et al. Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med. 2001 Jan;163(1):210-7.
3. Patel S, Takagi KI, Suzuki J, et al. RhoGTPase Activation Is a Key Step in Renal Epithelial Mesenchymal Transdifferentiation. J Am Soc Nephrol. 2005 Jul; 16(7): 1977-84.
4. Masamune A, Kikuta K, Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells. Br J Pharmacol. 2003 Dec; 140(7): 1292-302.
5. Tada S, Iwamoto H, Nakamuta M,et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol. 2001 Apr; 34(4): 529-36.
6. Murata T, Arii S, Mori A, et al. Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis. J Surg Res.2003 Sep; 114(1): 64-71.
7.王波,王天才,梁扩寰。细胞因子RhoA在实验性大鼠肝纤维化形成过程中的作用机制。中华消化杂志,2004,7,24(7):414-417。
8. Izquierdo M.Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther. 2005 Mar; 12(3): 217-27.
9. Cheng JC, Moore TB, Sakatomo KM.RNA interference and human disease. Mol Genet Metab,2003,80: 122-128.
10. Elbashir SM, Harborth J, Lendeckel W,et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001 May 24; 411(6836): 494-8.
11. Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver;collagens and glycoproteins. Sem Liver Dis, 1990; 10(1):1
12. Thompson KC, Trowern A, Fowell A, et al. Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro. Hepatology. 1998 Dec; 28(6): 1518-24.
13. Anne J. Ridley.Rho GTPases and cell migration. J Cell Sci. 2001 Aug; 114(Pt 15): 2713-22.
14. Holen T, Amarzguioui M, Wiiger MT,et al. Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor.Nucleic Acids Res. 2002 Apr 15; 30(8): 1757-66.
1. Etienne-Manneville S, Hall A.Rho GTPase in cell biology.Nature.2002 Dec 12;420(6916):629-35.
2. Penzes P, Johnson RC, Kambampati V, et al. Distinct roles for the two Rho GDP/GTP exchange factor domains of kalivin in regulation of neurite growth and neuronal morphology[J].J Neurosic.2001,21(21):8426-8434.
3. Marinissen MJ, Gutkind JS. Scaffold proteins dictate Rho GTPase-signaling specificity. Trends Biochem Sci. 2005 Aug;30(8):423-6.
4. Hocking DC,Sottile J,Langebach KJ.Stimulation of integrin-mediated cell contractility by fibronectin polymerization.J Biol Chem,2000,275(14):10673-10682.
5. Tada S, Iwamoto H, Nakamuta M,et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.J Hepatol.2001 Apr; 34(4):529-36.
6. Lee JS, Kang Decker N, Chatterjee S, et al. Mechanisms of nitric oxide interplay with Rho GTPase family members in modulation of actin membrane dynamics in pericytes and fibroblasts. Am J Pathol. 2005 Jun;166(6):1861-70.
7. Kanno K, Tazuma S, Nishioka T, et al.Angiotensin II participates in hepatic inflammation and fibrosis through MCP-1 expression. Dig Dis Sci. 2005 May;50(5):942-8.
8. Masamune A, Kikuta K, Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells.Br J Pharmacol.2003 Dec;140(7):1292-302.
9. Bourgier C, Haydont V, Milliat F, et al. Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut. 2005 Mar; 54(3):336-43.
10. Sumita C, Yamane M, Matsuda T, et al. Platelet activating factor induces cytoskeletal reorganization through Rho family pathway in THP-1 macrophages. FEBS Lett. 2005 Jul 18; 579(18): 4038-42.
11. Touyz RM. Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol. 2005 Jul;90(4):449-55.
12. Wang YX, da Cunha V, Martin-McNulty B, et al. Inhibition of Rho-kinase by fasudil attenuatedangiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice. Eur J Pharmacol. 2005 Apr 11;512(2-3):215-22.
13. Hattori T, Shimokawa H, Higashi M, et al. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation. 2004 May 11; 109(18): 2234-9.
14. Mukai Y, Shimokawa H, Matoba T, et al. Involvement of Rho-kinase in hypertensive vascular diseases novel therapeutic target in hypertension[J].FASEB J,2001,15(6): 1062-1064.
15. Kobayashi N, Horinaka S, Mita S, et al. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts.Cardiovasc Res.2002 Sep; 55(4): 757-67.
16. Patel S, Takagi KI, Suzuki J, et al. RhoGTPase Activation Is a Key Step in Renal Epithelial Mesenchymal Transdifferentiation.J Am Soc Nephrol.2005 Jul; 16(7): 1977-84.
17. Shimizu Y, Dobashi K, Iizuka K, et al. Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med. 2001 Jan; 163(1): 210-7.
18. Bogatkevich GS, Tourkina E, Abrams CS, et al. Contractile activity and smooth muscle alpha-actin organization in thrombin-induced human lung myofibroblasts. Am J Physiol Lung Cell Mol Physiol.2003 Aug; 285(2): L334-43.
19. Hyvelin JM,Howell K,Nichol A,et al.Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation. Circ Res. 2005 Jun 16;
20. Kreiselmeier NE, Kraynack NC, Corey DA, et al. Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2003 Dec; 285(6): L1286-95.
21. Nakayamada S,Kurose H,Saito K, et al. Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts. Arthritis Res Ther. 2005; 7(3):R476-84.
22. Murata T, Arii S, Mori A, et al. Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis. J Surg Res.2003 Sep; 114(1): 64-71.
23. Ikeda H, Nagashima K, Yanase M, et al. Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2003 Nov; 285(5):G880-6.
24. Fukushima M, Nakamuta M, Kohjima M, et al.Fasudil hydrochloride hydrate, a Rho-kinase(ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells.Liver Int.2005 Aug; 25(4): 829-38.
25. Higashi N,Kohjima M,Fukushima M,et al. Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells. J Lab Clin Med. 2005 Jun; 145(6): 316-22.
26. Porter KE, Turner NA, O'Regan DJ, et al. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res. 2004 Mar 1; 61(4): 745-55.
27. Mita S, Kobayashi N, Yoshida K, et al. Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertens. 2005 Jan;23(1):87-96.
28. Nagatoya K, Moriyama T, Kawada N, et al.Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction [J].Kidney Int,2002, 61(5): 1684-1695.
29. Satoh S, Yamaguchi T, Hitomi A, et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol.2002 Nov 29; 455(2-3): 169-74.
30. Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M. Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins). Br J Pharmacol.2001 Aug; 133(7): 1172-80.
2. Shimizu Y, Dobashi K, Iizuka K, et al. Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med. 2001 Jan;163(1):210-7.
3. Patel S, Takagi KI, Suzuki J, et al. RhoGTPase Activation Is a Key Step in Renal Epithelial Mesenchymal Transdifferentiation. J Am Soc Nephrol. 2005 Jul; 16(7): 1977-84.
4. Masamune A, Kikuta K, Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells. Br J Pharmacol. 2003 Dec; 140(7): 1292-302.
5. Tada S, Iwamoto H, Nakamuta M,et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol. 2001 Apr; 34(4): 529-36.
6. Murata T, Arii S, Mori A, et al. Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis. J Surg Res.2003 Sep; 114(1): 64-71.
7.王波,王天才,梁扩寰。细胞因子RhoA在实验性大鼠肝纤维化形成过程中的作用机制。中华消化杂志,2004,7,24(7):414-417。
8. Izquierdo M.Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther. 2005 Mar; 12(3): 217-27.
9. Cheng JC, Moore TB, Sakatomo KM.RNA interference and human disease. Mol Genet Metab,2003,80: 122-128.
10. Elbashir SM, Harborth J, Lendeckel W,et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001 May 24; 411(6836): 494-8.
11. Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver;collagens and glycoproteins. Sem Liver Dis, 1990; 10(1):1
12. Thompson KC, Trowern A, Fowell A, et al. Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro. Hepatology. 1998 Dec; 28(6): 1518-24.
13. Anne J. Ridley.Rho GTPases and cell migration. J Cell Sci. 2001 Aug; 114(Pt 15): 2713-22.
14. Holen T, Amarzguioui M, Wiiger MT,et al. Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor.Nucleic Acids Res. 2002 Apr 15; 30(8): 1757-66.
1. Etienne-Manneville S, Hall A.Rho GTPase in cell biology.Nature.2002 Dec 12;420(6916):629-35.
2. Penzes P, Johnson RC, Kambampati V, et al. Distinct roles for the two Rho GDP/GTP exchange factor domains of kalivin in regulation of neurite growth and neuronal morphology[J].J Neurosic.2001,21(21):8426-8434.
3. Marinissen MJ, Gutkind JS. Scaffold proteins dictate Rho GTPase-signaling specificity. Trends Biochem Sci. 2005 Aug;30(8):423-6.
4. Hocking DC,Sottile J,Langebach KJ.Stimulation of integrin-mediated cell contractility by fibronectin polymerization.J Biol Chem,2000,275(14):10673-10682.
5. Tada S, Iwamoto H, Nakamuta M,et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.J Hepatol.2001 Apr; 34(4):529-36.
6. Lee JS, Kang Decker N, Chatterjee S, et al. Mechanisms of nitric oxide interplay with Rho GTPase family members in modulation of actin membrane dynamics in pericytes and fibroblasts. Am J Pathol. 2005 Jun;166(6):1861-70.
7. Kanno K, Tazuma S, Nishioka T, et al.Angiotensin II participates in hepatic inflammation and fibrosis through MCP-1 expression. Dig Dis Sci. 2005 May;50(5):942-8.
8. Masamune A, Kikuta K, Satoh M, et al. Rho kinase inhibitors block activation of pancreatic stellate cells.Br J Pharmacol.2003 Dec;140(7):1292-302.
9. Bourgier C, Haydont V, Milliat F, et al. Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut. 2005 Mar; 54(3):336-43.
10. Sumita C, Yamane M, Matsuda T, et al. Platelet activating factor induces cytoskeletal reorganization through Rho family pathway in THP-1 macrophages. FEBS Lett. 2005 Jul 18; 579(18): 4038-42.
11. Touyz RM. Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol. 2005 Jul;90(4):449-55.
12. Wang YX, da Cunha V, Martin-McNulty B, et al. Inhibition of Rho-kinase by fasudil attenuatedangiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice. Eur J Pharmacol. 2005 Apr 11;512(2-3):215-22.
13. Hattori T, Shimokawa H, Higashi M, et al. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation. 2004 May 11; 109(18): 2234-9.
14. Mukai Y, Shimokawa H, Matoba T, et al. Involvement of Rho-kinase in hypertensive vascular diseases novel therapeutic target in hypertension[J].FASEB J,2001,15(6): 1062-1064.
15. Kobayashi N, Horinaka S, Mita S, et al. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts.Cardiovasc Res.2002 Sep; 55(4): 757-67.
16. Patel S, Takagi KI, Suzuki J, et al. RhoGTPase Activation Is a Key Step in Renal Epithelial Mesenchymal Transdifferentiation.J Am Soc Nephrol.2005 Jul; 16(7): 1977-84.
17. Shimizu Y, Dobashi K, Iizuka K, et al. Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med. 2001 Jan; 163(1): 210-7.
18. Bogatkevich GS, Tourkina E, Abrams CS, et al. Contractile activity and smooth muscle alpha-actin organization in thrombin-induced human lung myofibroblasts. Am J Physiol Lung Cell Mol Physiol.2003 Aug; 285(2): L334-43.
19. Hyvelin JM,Howell K,Nichol A,et al.Inhibition of Rho-Kinase Attenuates Hypoxia-Induced Angiogenesis in the Pulmonary Circulation. Circ Res. 2005 Jun 16;
20. Kreiselmeier NE, Kraynack NC, Corey DA, et al. Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2003 Dec; 285(6): L1286-95.
21. Nakayamada S,Kurose H,Saito K, et al. Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts. Arthritis Res Ther. 2005; 7(3):R476-84.
22. Murata T, Arii S, Mori A, et al. Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis. J Surg Res.2003 Sep; 114(1): 64-71.
23. Ikeda H, Nagashima K, Yanase M, et al. Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2003 Nov; 285(5):G880-6.
24. Fukushima M, Nakamuta M, Kohjima M, et al.Fasudil hydrochloride hydrate, a Rho-kinase(ROCK) inhibitor, suppresses collagen production and enhances collagenase activity in hepatic stellate cells.Liver Int.2005 Aug; 25(4): 829-38.
25. Higashi N,Kohjima M,Fukushima M,et al. Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells. J Lab Clin Med. 2005 Jun; 145(6): 316-22.
26. Porter KE, Turner NA, O'Regan DJ, et al. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res. 2004 Mar 1; 61(4): 745-55.
27. Mita S, Kobayashi N, Yoshida K, et al. Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertens. 2005 Jan;23(1):87-96.
28. Nagatoya K, Moriyama T, Kawada N, et al.Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction [J].Kidney Int,2002, 61(5): 1684-1695.
29. Satoh S, Yamaguchi T, Hitomi A, et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol.2002 Nov 29; 455(2-3): 169-74.
30. Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M. Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins). Br J Pharmacol.2001 Aug; 133(7): 1172-80.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |