尾加压素Ⅱ在大鼠肾间质纤维化发生发展中的作用及其机制的研究
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摘要
肾间质纤维化是进展到终末期肾衰竭的共同途径和主要病理学基础，主要病理学变化是肾间质成纤维细胞活化，分泌大量细胞外基质(ECM)，沉积于肾间质，导致肾间质纤维化。近年来，尾加压素Ⅱ(UⅡ)在肾脏疾病中的病理生理作用受到关注，UⅡ及其受体在肾内广泛分布，且具有多种生物学作用。但UⅡ在肾间质纤维化发生发展中的作用尚未阐明。本研究从体内、体外实验两方面进行一系列研究，旨在揭示UⅡ在大鼠肾间质纤维化形成过程中的作用，并探讨作用的机制。
在整体水平上，采用单侧输尿管梗阻(UUO)方法诱发大鼠肾间质纤维化模型。实验结果表明，UUO组大鼠血肌酐、尿肌酐、尿素氮水平增高；HE染色及masson染色证实UUO组大鼠肾间质炎细胞浸润，间质扩张，胶原呈带状明显增生；免疫组化、RT-PCR和Western blot结果表明，UUO组大鼠肾组织UⅡ及其受体GPR14含量明显升高，且与致纤维化因子tTG及TGF-β1呈正相关。
肾间质成纤维细胞是纤维化时的主要效应细胞，大鼠肾间质成纤维细胞(NRK-49F)容易培养可传代，是一个比较理想的细胞模型。采用MTT法及流式细胞术研究发现UⅡ对NRK-49F的促增殖作用具有浓度依赖性和时间依赖性；UⅡ提高NRK-49F细胞α-SMA的表达，促进其向肌成纤维细胞转分化；UⅡ增加ECM的合成及分泌；提高TGF-β1、CTGF、及tTG的mRNA的表达及蛋白水平；RNA干扰技术的应用进一步证实了UⅡ受体GPR14的重要作用，GPR14基因干扰后，UⅡ的促TGF-β1及CTGF合成明显降低。钙通道阻断剂尼莫地平、钙离子鳌合剂EDTA及UⅡ抗体能不同程度的阻断UⅡ的作用。这些研究结果表明，UⅡ具有促进肾脏成纤维细胞增殖、转分化、ECM沉积及分泌致纤维化活性因子的作用，为研究肾间质纤维化的发生机制和防治措施提供了新的理论依据。
UrotensinⅡ(UⅡ) is a cyclic neuropeptide that was first isolated from the caudalneurosecretory system of teleost fish. UⅡcombined with its specific receptor GPR14 cantrigger various biological events that play an important pathophysiological role. UⅡandGPR14 widely exist in the cardiovascular system, kidney, liver, brain and so on. UⅡis themost potent vasoconstrictor peptide to date, it has identified to have cardiovascular actions andcontribute to vasoconstriction. UⅡis not only a potent vasoconstrictor peptide, but also havethe effect of non-hemodynamics. With the study an increasing amount of evidence hasaccumulated for the presence of both UⅡand its receptor in kidney, UⅡis secreted andexcreted by kidney and it acts as a growth factor for the renal epithelial cells by autocrine and(or) paracrine ways. In addition, UⅡacts as a mitogen and promotes the proliferation andDNA synthesis of renal intercapillary and tubular cells. All of the above results suggest thatUⅡis associated with physiopathology and pathogenesis of the kidney diseases. However, therole and the mechanism of UⅡin renal interstitial fibrosis have not been addressed.
Renal interstitial fibrosis, which is the common pathway and main pathology foundationfor almost all kidney disease, is the common turnover of various kinds of chronic renopathy. Itis characterized by renal interstitial fibroblasts proliferation and excess extracellular matrix(ECM) accumulation in the renal interstitium. It is reported that UⅡinvolved in the adjustmentof the cardiomyocyte hypertrophy and cardiac fibrosis. Well, the study on effects of UⅡonrenal interstitial fibrosis and its mechanism in rats have not been reported. So it has importantsignificant to discover the effects of urotensinⅡon renal interstitial fibrosis and its mechanism,and find a new target for clinical treatment of renal disease by antagonism of UⅡ.
In the present study, the renal interstitial fibroblast model induced by unilateral ureteralobstruction (UUO) in rats was established and the rat renal interstitium fibroblasts NRK-49Fwere cultured in vitro. The light microscope, immunohistochemistry, flow cytometry, ELISA, RT-PCR, Western blot and RNA interference techniques were employed, and the followingissues were investigated: the contents of both UⅡand its receptor in renal medulla of renalinterstitial fibrosis model induced by UUO; effects of UⅡon proliferation and cell cycle,transdifferentiation and ECM accumulate in NRK-49F cells; the relationship of UⅡand somebioactive compound like TGF-β1, CTGF; the effects of Nimodipine, EDTA and UⅡantibodyon NRK-49F cells. The aim of these investigations was to reveal the roles of UⅡin thedevelopment and progression of renal interstitial fibrosis and possible action mechanism, andto offer new clue for prevention and cure of interstitial fibroblast.
The main results of the present study are as follows:
1. The left kidney which be ligated with ureter was bigger than the right, the renalcortex was thinner than normal in section, renal pelvis and renal calices were stretched. Allthese changes were obvious in the UUO rat (obstruction for 7 days, UUO 7d).
2. The pathological features with HE staining included renal interstitium edema andinflammatory cell infiltration in the UUO 3d. When in the UUO 7d, prominent interstitialexpansion, inflammatory cell infiltration, renal tubules show varying degrees of vacuolardegeneration, necrosis and cast formation, renal tubule expansion, interstitial collagen wereaccumulation.
3. The pathological features with Masson’s trichrome-staining included collagengirdle-shaped in the interstitial of kidney which be ligated.
4. The urine creatinine, serum creatinine and blood urea nitrogen contents weresignificantly increased in the UUO 7d compared with the Sham group (P<0.05).
5. Immunohistochemical detection showed that the area and intensity of immunologicalstaining for UⅡ, GPR14, and tTG were increased in the UUO group(3d and 7d) comparedwith the Sham group (P<0.01).
6. Compared with the Sham group, the expression levels of UⅡand GPR14 mRNA andprotein in UUO group(3d and 7d) were significantly increased ( P<0.01). The expressions ofUⅡmRNA in UUO group were positively correlated with Scr contents (r＝0.601, P=0.039)and Ucr contents (r＝0.599, P=0.04) that reflected the renal function injury.
7. UⅡexerted the stimulative effect on NRK-49F cell proliferation and DNA synthesiswhen UⅡat concentrations of 10-9 and 10-8mol/L, compared with the Sham group (P<0.01).
8. UⅡpromoted the transdifferentiation of NRK-49 F cells by stimulate the expressionof theα-SMA and increased the accumulation of ECM, enhanced the TGF-β1, CTGF and tTG mRNA expression in NRK-49F cells. Especially in 10-9mol/L and 10-8mol/L of UⅡgroupcompared with the control group.
9. Nimodipine, EDTA and UⅡantibody treatment weakend the effect includingNRK-49F cell proliferation, ECM accumulate, the expression of TGF-β1、CTGF and tTG..
10. RNA interference of GPR14 suppressed an increase in TGF-β1 and CTGF mRNAexpression caused by UⅡ.
The conclusions of this study are as follows:
1. Renal interstitial fibrosis animal model is established by UUO in rats.
2. UUO can induce the rats with renal function injury, kidney index increasing, renalfeature changed and the accumulation of the collagen.
3. UⅡand GPR14 mRNA and protein are significantly enhanced in UUO groupcompared with the Sham group, it may suggest UⅡand GPR14 have important roles in thedevelopment of the renal fibrosis.
4. UⅡis able to cause proliferation and DNA synthesis of NRK-49F cells in aconcentration-dependent manner, Calcium ion inflow may partly mediate UⅡ-induced cellmultiplication in NRK-49F cells.
5. UⅡincreases the expression of ColI、Col III and FN in NRK-49F cells, promote theexpression ofα-SMA, thereby promote the transdifferentiatie of the NRK-49F cells.
6. The effects of UⅡcan be blocked partly by Nimodipine, EDTA and UⅡantibody.especially the effect of the UⅡantibody compared with the other group.
The creative points of the present study are: it is studied that UⅡhad intimaterelationships with renal diease, well, the mechanism of which UⅡplayed in the renalinterstitial fibrosis has not been reported. and its receptor GPR14 increase significantly in themodel of renal interstitial fibrosis induced by UUO; UⅡcan promote the proliferation andDNA synthesize of NRK-49F; UⅡcan increase the production of ECM andtransdifferentiation of of NRK-49F; UⅡis involved in renal interstitial fibrosis; conbined withRNAi, it is demonstrated that UⅡcan increased the expression of TGF-β1 in NRK-49F cell byinduced of GPR14.
在整体水平上，采用单侧输尿管梗阻(UUO)方法诱发大鼠肾间质纤维化模型。实验结果表明，UUO组大鼠血肌酐、尿肌酐、尿素氮水平增高；HE染色及masson染色证实UUO组大鼠肾间质炎细胞浸润，间质扩张，胶原呈带状明显增生；免疫组化、RT-PCR和Western blot结果表明，UUO组大鼠肾组织UⅡ及其受体GPR14含量明显升高，且与致纤维化因子tTG及TGF-β1呈正相关。
肾间质成纤维细胞是纤维化时的主要效应细胞，大鼠肾间质成纤维细胞(NRK-49F)容易培养可传代，是一个比较理想的细胞模型。采用MTT法及流式细胞术研究发现UⅡ对NRK-49F的促增殖作用具有浓度依赖性和时间依赖性；UⅡ提高NRK-49F细胞α-SMA的表达，促进其向肌成纤维细胞转分化；UⅡ增加ECM的合成及分泌；提高TGF-β1、CTGF、及tTG的mRNA的表达及蛋白水平；RNA干扰技术的应用进一步证实了UⅡ受体GPR14的重要作用，GPR14基因干扰后，UⅡ的促TGF-β1及CTGF合成明显降低。钙通道阻断剂尼莫地平、钙离子鳌合剂EDTA及UⅡ抗体能不同程度的阻断UⅡ的作用。这些研究结果表明，UⅡ具有促进肾脏成纤维细胞增殖、转分化、ECM沉积及分泌致纤维化活性因子的作用，为研究肾间质纤维化的发生机制和防治措施提供了新的理论依据。
UrotensinⅡ(UⅡ) is a cyclic neuropeptide that was first isolated from the caudalneurosecretory system of teleost fish. UⅡcombined with its specific receptor GPR14 cantrigger various biological events that play an important pathophysiological role. UⅡandGPR14 widely exist in the cardiovascular system, kidney, liver, brain and so on. UⅡis themost potent vasoconstrictor peptide to date, it has identified to have cardiovascular actions andcontribute to vasoconstriction. UⅡis not only a potent vasoconstrictor peptide, but also havethe effect of non-hemodynamics. With the study an increasing amount of evidence hasaccumulated for the presence of both UⅡand its receptor in kidney, UⅡis secreted andexcreted by kidney and it acts as a growth factor for the renal epithelial cells by autocrine and(or) paracrine ways. In addition, UⅡacts as a mitogen and promotes the proliferation andDNA synthesis of renal intercapillary and tubular cells. All of the above results suggest thatUⅡis associated with physiopathology and pathogenesis of the kidney diseases. However, therole and the mechanism of UⅡin renal interstitial fibrosis have not been addressed.
Renal interstitial fibrosis, which is the common pathway and main pathology foundationfor almost all kidney disease, is the common turnover of various kinds of chronic renopathy. Itis characterized by renal interstitial fibroblasts proliferation and excess extracellular matrix(ECM) accumulation in the renal interstitium. It is reported that UⅡinvolved in the adjustmentof the cardiomyocyte hypertrophy and cardiac fibrosis. Well, the study on effects of UⅡonrenal interstitial fibrosis and its mechanism in rats have not been reported. So it has importantsignificant to discover the effects of urotensinⅡon renal interstitial fibrosis and its mechanism,and find a new target for clinical treatment of renal disease by antagonism of UⅡ.
In the present study, the renal interstitial fibroblast model induced by unilateral ureteralobstruction (UUO) in rats was established and the rat renal interstitium fibroblasts NRK-49Fwere cultured in vitro. The light microscope, immunohistochemistry, flow cytometry, ELISA, RT-PCR, Western blot and RNA interference techniques were employed, and the followingissues were investigated: the contents of both UⅡand its receptor in renal medulla of renalinterstitial fibrosis model induced by UUO; effects of UⅡon proliferation and cell cycle,transdifferentiation and ECM accumulate in NRK-49F cells; the relationship of UⅡand somebioactive compound like TGF-β1, CTGF; the effects of Nimodipine, EDTA and UⅡantibodyon NRK-49F cells. The aim of these investigations was to reveal the roles of UⅡin thedevelopment and progression of renal interstitial fibrosis and possible action mechanism, andto offer new clue for prevention and cure of interstitial fibroblast.
The main results of the present study are as follows:
1. The left kidney which be ligated with ureter was bigger than the right, the renalcortex was thinner than normal in section, renal pelvis and renal calices were stretched. Allthese changes were obvious in the UUO rat (obstruction for 7 days, UUO 7d).
2. The pathological features with HE staining included renal interstitium edema andinflammatory cell infiltration in the UUO 3d. When in the UUO 7d, prominent interstitialexpansion, inflammatory cell infiltration, renal tubules show varying degrees of vacuolardegeneration, necrosis and cast formation, renal tubule expansion, interstitial collagen wereaccumulation.
3. The pathological features with Masson’s trichrome-staining included collagengirdle-shaped in the interstitial of kidney which be ligated.
4. The urine creatinine, serum creatinine and blood urea nitrogen contents weresignificantly increased in the UUO 7d compared with the Sham group (P<0.05).
5. Immunohistochemical detection showed that the area and intensity of immunologicalstaining for UⅡ, GPR14, and tTG were increased in the UUO group(3d and 7d) comparedwith the Sham group (P<0.01).
6. Compared with the Sham group, the expression levels of UⅡand GPR14 mRNA andprotein in UUO group(3d and 7d) were significantly increased ( P<0.01). The expressions ofUⅡmRNA in UUO group were positively correlated with Scr contents (r＝0.601, P=0.039)and Ucr contents (r＝0.599, P=0.04) that reflected the renal function injury.
7. UⅡexerted the stimulative effect on NRK-49F cell proliferation and DNA synthesiswhen UⅡat concentrations of 10-9 and 10-8mol/L, compared with the Sham group (P<0.01).
8. UⅡpromoted the transdifferentiation of NRK-49 F cells by stimulate the expressionof theα-SMA and increased the accumulation of ECM, enhanced the TGF-β1, CTGF and tTG mRNA expression in NRK-49F cells. Especially in 10-9mol/L and 10-8mol/L of UⅡgroupcompared with the control group.
9. Nimodipine, EDTA and UⅡantibody treatment weakend the effect includingNRK-49F cell proliferation, ECM accumulate, the expression of TGF-β1、CTGF and tTG..
10. RNA interference of GPR14 suppressed an increase in TGF-β1 and CTGF mRNAexpression caused by UⅡ.
The conclusions of this study are as follows:
1. Renal interstitial fibrosis animal model is established by UUO in rats.
2. UUO can induce the rats with renal function injury, kidney index increasing, renalfeature changed and the accumulation of the collagen.
3. UⅡand GPR14 mRNA and protein are significantly enhanced in UUO groupcompared with the Sham group, it may suggest UⅡand GPR14 have important roles in thedevelopment of the renal fibrosis.
4. UⅡis able to cause proliferation and DNA synthesis of NRK-49F cells in aconcentration-dependent manner, Calcium ion inflow may partly mediate UⅡ-induced cellmultiplication in NRK-49F cells.
5. UⅡincreases the expression of ColI、Col III and FN in NRK-49F cells, promote theexpression ofα-SMA, thereby promote the transdifferentiatie of the NRK-49F cells.
6. The effects of UⅡcan be blocked partly by Nimodipine, EDTA and UⅡantibody.especially the effect of the UⅡantibody compared with the other group.
The creative points of the present study are: it is studied that UⅡhad intimaterelationships with renal diease, well, the mechanism of which UⅡplayed in the renalinterstitial fibrosis has not been reported. and its receptor GPR14 increase significantly in themodel of renal interstitial fibrosis induced by UUO; UⅡcan promote the proliferation andDNA synthesize of NRK-49F; UⅡcan increase the production of ECM andtransdifferentiation of of NRK-49F; UⅡis involved in renal interstitial fibrosis; conbined withRNAi, it is demonstrated that UⅡcan increased the expression of TGF-β1 in NRK-49F cell byinduced of GPR14.
引文
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