尾加压素Ⅱ在糖尿病肾脏病变中作用及其分子机制的研究
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摘要
尾加压素Ⅱ(UⅡ)是目前已知的体内最强的缩血管活性肽。近年来大量研究证据表明,除血流动力学作用外,UⅡ还具有非血流动力学效应,在多种疾病的发生发展中具有重要病理生理意义。糖尿病肾病(DN)是糖尿病最常见的慢性并发症之一,发病机制尚未完全阐明,且缺乏有效防治手段。有研究发现,UⅡ及其受体在DN患者肾组织中呈明显高表达,但UⅡ在DN发病中的作用及其分子机制目前尚不清楚。
本研究应用免疫组织化学、细胞生物学、流式细胞术、酶联免疫吸附实验、RT-PCR和RNA干扰等技术,研究了UⅡ及其受体在DN肾组织中的表达,UⅡ对肾小球系膜细胞(MC)增殖及细胞外基质分泌的影响,UⅡ与某些致DN因素之间的关系等,旨在探讨UⅡ在DN发生发展中的作用及其可能的分子机制,为DN防治提供实验依据。
本研究结果表明,链脲佐菌素(STZ)诱发大鼠糖尿病肾脏病变时,肾组织UⅡ及其受体GPR14 mRNA表达水平明显增加;一定浓度UⅡ对MC具有促增殖作用,UⅡ阻断药能抑制该效应;糖基化终产物(AGEs)、转化生长因子β1(TGF-β1)及血管紧张素Ⅱ(AngⅡ)能增强MC UⅡ及其受体GPR14 mRNA的表达。GPR14基因干扰可减轻UⅡ对TGF-β1 mRNA表达的刺激作用。这些结果提示,UⅡ在DN发生发展中具有一定作用,为研究DN防治措施提供了新的理论依据。
UrotensinⅡ(urotensinⅡ,UⅡ) is a cycic neuropeptide initially isolated from the caudal neurosecretory system of teleost fish, its human homolog (hUⅡ) has subsequently been cloned in 1998. UⅡis the most potent vasoconstrictive peptide ever identified, it widely exists in the brain, cardiovascular system, liver, kidney, and so on from mollusks to mammals. G-protein-couple receptor is its specific receptor, originally termed GPR14. UⅡexerts biological effects via interaction with its receptor GPR14. Accumulating evidences indicate that UⅡshows both hemodynamic effects and non-hemodynamic effects, such as stimulating cell proliferation and regulating endocrine and metabolic, etc. So UⅡplays an important pathophysiological role in the development and progression of some diseases.
Especially, its non-hemodynamic effects have become the focus of attention. Diabetic nephropathy (DN) is one of important microvascular complications of diabetes, its pathogenesis is complex and the consequences could be serious. Because of the lack of effective prevention and treatment means, it has become the common cause of end-stage renal disease. DN can also increase the incidence of cardiovascular events and mortality, it is one of the important disabled and death reasons of patients with diabetes.
The main pathological changes of diabetic nephropathy is glomerular hypertrophy, hyperfiltration and the accumulation of extracellular matrix in the initial stage and glomerular sclerosis in later stage. Mesangial cells (MC) is the central factor. Usually glomerular sclerosis is divided into nodular, exudative and diffuse three kinds of types, the nodular type is characteristic for DN. The pathogenesis of DN is complex and still not clear, it is generally considered that it has relations with genetic factors, high blood sugar-related metabolic disorders, etc. AGEs, TGF-β1 and AngⅡare the important factors in the development and progression of DN.
The recent studies showed that expression of UⅡand GPR14 mRNA in kidney was exceptionally upregulated in patients with diabetic nephropathy. In addition, UⅡcan be secreted and excreted by kidney. Acts as a growth factor, UⅡcan promote the proliferation of mesangial cells. These suggest that UⅡmay be involved in the occurrence and development of DN. However, the role of UⅡin pathogenesis of diabetic nephropathy and its molecular mechanism have not been elucidated.
In the present study, diabetic renal lesion was prepared in rats using streptozotocin by intraperitoneal injection, and cultured rat mesangial cells were utilized, and the following issuses were investigated:①the contents of both UⅡand its receptor in renal cortex of rat at different periods of diabetes (2~12 weeks);②effects of UⅡon proliferation in MC;③the relationship between AGEs, TGF-β1 and AngⅡwith UⅡ;④the effects of RNA interference of GPR14 on the expression of TGF-β1 mRNA caused by UⅡ.
The main findings are as follows:
1. It was detected that the body weight reduced, the kidney weight, the kidney volume and the kidney index significantly increased in rats at different periods of diabetes compared with the control group (P<0.05).
2. The GSP, Glu, Scr and 24 hour urinary protein contents were obviously increased in diabetic rats compared with the control group.
3. Immunohistochemical detection showed that the area and intensity of immunological staining for UⅡ, GPR14, TGF-β1, FN and ColⅣwere increased in kidney of diabetic rats compared with the control group (P<0.05).
4. Compared with the control group, the expression of UⅡand GPR14 mRNA in renal cortex of rats with DM2W and DM4W had no obviously change (P>0.05), but these were significantly increased in renal cortex of rats with DM8W and DM12W (P<0.05).
5. UⅡat concentration 10~(-9) and 10~(-8) mol/L promoted the proliferation and DNA synthesis of mesangial cells, Treatment wih nicardipine, ethylene diaine tetraacetic acid (EDTA) and anti-UⅡantibody weakend the effect of UⅡ.
6. The expression of UⅡand GPR14 mRNA in AGEs-, TGF-β1- or AngⅡ-treated MC was significantly increased, anti-TGF-β1 antibody reduced the effect caused by TGF-β1.
7. UⅡat concentration 10-9 and 10-8 mol/L markedly increased the level of FN, ColⅣ, TGF-β1 and AngⅡin MC culture medium.
8. UⅡpromoted the expressions of FN, ColⅣ, TGF-β1 and AngⅡ(AT1) (P<0.05). The increased expressions were significantly reduced by addition of nicardipine, ethylene diaine tetraacetic acid (EDTA) and anti-UⅡantibody.
9. RNA interference of GPR14 suppressed the increased expression of TGF-β1 mRNA caused by UⅡ.
The main conclusions are as follows:
1. The expression of UⅡand GPR14 in renal cortex is significantly increased in diabetic rats prepared using streptozotocin by intraperitoneal injection.
2. UⅡat certain concentrations can promote the proliferation of mesangial cells, the action may partly be mediated by calcium ion inflow.
3. AGEs can significantly increase the expression of UⅡand GPR14 mRNA in MC.
4. UⅡat certain concentrations can promote the secretion and mRNA expressions of FN, ColⅣ, TGF-β1 and AngⅡ. TGF-β1 and AngⅡcan also increase the expression of UⅡand GPR14 mRNA in MC. UⅡ,TGF-β1 and AngⅡmay have a synergistic effect in the occurrence and development of diabetic nephropathy.
5. The effect of UⅡincreased TGF-β1 mRNA expression in MC is mediated by UⅡreceptor GPR14.
This originality of dissertation lies in the following:
It is demonstrated that the expressions of UⅡand GPR14 protein and mRNA in renal cortex in streptozotocin-induced diabetic rats are significantly increased; UⅡat certain concentrations can promote the proliferation and DNA synthesis of mesangial cells, and increase the secretion and mRNA expression of FN, ColⅣ, TGF-β1 and AngⅡ(AT_1). The findings suggest that UⅡmay directly or indirectly participate in the development and progression of diabetic nephropathy.
本研究应用免疫组织化学、细胞生物学、流式细胞术、酶联免疫吸附实验、RT-PCR和RNA干扰等技术,研究了UⅡ及其受体在DN肾组织中的表达,UⅡ对肾小球系膜细胞(MC)增殖及细胞外基质分泌的影响,UⅡ与某些致DN因素之间的关系等,旨在探讨UⅡ在DN发生发展中的作用及其可能的分子机制,为DN防治提供实验依据。
本研究结果表明,链脲佐菌素(STZ)诱发大鼠糖尿病肾脏病变时,肾组织UⅡ及其受体GPR14 mRNA表达水平明显增加;一定浓度UⅡ对MC具有促增殖作用,UⅡ阻断药能抑制该效应;糖基化终产物(AGEs)、转化生长因子β1(TGF-β1)及血管紧张素Ⅱ(AngⅡ)能增强MC UⅡ及其受体GPR14 mRNA的表达。GPR14基因干扰可减轻UⅡ对TGF-β1 mRNA表达的刺激作用。这些结果提示,UⅡ在DN发生发展中具有一定作用,为研究DN防治措施提供了新的理论依据。
UrotensinⅡ(urotensinⅡ,UⅡ) is a cycic neuropeptide initially isolated from the caudal neurosecretory system of teleost fish, its human homolog (hUⅡ) has subsequently been cloned in 1998. UⅡis the most potent vasoconstrictive peptide ever identified, it widely exists in the brain, cardiovascular system, liver, kidney, and so on from mollusks to mammals. G-protein-couple receptor is its specific receptor, originally termed GPR14. UⅡexerts biological effects via interaction with its receptor GPR14. Accumulating evidences indicate that UⅡshows both hemodynamic effects and non-hemodynamic effects, such as stimulating cell proliferation and regulating endocrine and metabolic, etc. So UⅡplays an important pathophysiological role in the development and progression of some diseases.
Especially, its non-hemodynamic effects have become the focus of attention. Diabetic nephropathy (DN) is one of important microvascular complications of diabetes, its pathogenesis is complex and the consequences could be serious. Because of the lack of effective prevention and treatment means, it has become the common cause of end-stage renal disease. DN can also increase the incidence of cardiovascular events and mortality, it is one of the important disabled and death reasons of patients with diabetes.
The main pathological changes of diabetic nephropathy is glomerular hypertrophy, hyperfiltration and the accumulation of extracellular matrix in the initial stage and glomerular sclerosis in later stage. Mesangial cells (MC) is the central factor. Usually glomerular sclerosis is divided into nodular, exudative and diffuse three kinds of types, the nodular type is characteristic for DN. The pathogenesis of DN is complex and still not clear, it is generally considered that it has relations with genetic factors, high blood sugar-related metabolic disorders, etc. AGEs, TGF-β1 and AngⅡare the important factors in the development and progression of DN.
The recent studies showed that expression of UⅡand GPR14 mRNA in kidney was exceptionally upregulated in patients with diabetic nephropathy. In addition, UⅡcan be secreted and excreted by kidney. Acts as a growth factor, UⅡcan promote the proliferation of mesangial cells. These suggest that UⅡmay be involved in the occurrence and development of DN. However, the role of UⅡin pathogenesis of diabetic nephropathy and its molecular mechanism have not been elucidated.
In the present study, diabetic renal lesion was prepared in rats using streptozotocin by intraperitoneal injection, and cultured rat mesangial cells were utilized, and the following issuses were investigated:①the contents of both UⅡand its receptor in renal cortex of rat at different periods of diabetes (2~12 weeks);②effects of UⅡon proliferation in MC;③the relationship between AGEs, TGF-β1 and AngⅡwith UⅡ;④the effects of RNA interference of GPR14 on the expression of TGF-β1 mRNA caused by UⅡ.
The main findings are as follows:
1. It was detected that the body weight reduced, the kidney weight, the kidney volume and the kidney index significantly increased in rats at different periods of diabetes compared with the control group (P<0.05).
2. The GSP, Glu, Scr and 24 hour urinary protein contents were obviously increased in diabetic rats compared with the control group.
3. Immunohistochemical detection showed that the area and intensity of immunological staining for UⅡ, GPR14, TGF-β1, FN and ColⅣwere increased in kidney of diabetic rats compared with the control group (P<0.05).
4. Compared with the control group, the expression of UⅡand GPR14 mRNA in renal cortex of rats with DM2W and DM4W had no obviously change (P>0.05), but these were significantly increased in renal cortex of rats with DM8W and DM12W (P<0.05).
5. UⅡat concentration 10~(-9) and 10~(-8) mol/L promoted the proliferation and DNA synthesis of mesangial cells, Treatment wih nicardipine, ethylene diaine tetraacetic acid (EDTA) and anti-UⅡantibody weakend the effect of UⅡ.
6. The expression of UⅡand GPR14 mRNA in AGEs-, TGF-β1- or AngⅡ-treated MC was significantly increased, anti-TGF-β1 antibody reduced the effect caused by TGF-β1.
7. UⅡat concentration 10-9 and 10-8 mol/L markedly increased the level of FN, ColⅣ, TGF-β1 and AngⅡin MC culture medium.
8. UⅡpromoted the expressions of FN, ColⅣ, TGF-β1 and AngⅡ(AT1) (P<0.05). The increased expressions were significantly reduced by addition of nicardipine, ethylene diaine tetraacetic acid (EDTA) and anti-UⅡantibody.
9. RNA interference of GPR14 suppressed the increased expression of TGF-β1 mRNA caused by UⅡ.
The main conclusions are as follows:
1. The expression of UⅡand GPR14 in renal cortex is significantly increased in diabetic rats prepared using streptozotocin by intraperitoneal injection.
2. UⅡat certain concentrations can promote the proliferation of mesangial cells, the action may partly be mediated by calcium ion inflow.
3. AGEs can significantly increase the expression of UⅡand GPR14 mRNA in MC.
4. UⅡat certain concentrations can promote the secretion and mRNA expressions of FN, ColⅣ, TGF-β1 and AngⅡ. TGF-β1 and AngⅡcan also increase the expression of UⅡand GPR14 mRNA in MC. UⅡ,TGF-β1 and AngⅡmay have a synergistic effect in the occurrence and development of diabetic nephropathy.
5. The effect of UⅡincreased TGF-β1 mRNA expression in MC is mediated by UⅡreceptor GPR14.
This originality of dissertation lies in the following:
It is demonstrated that the expressions of UⅡand GPR14 protein and mRNA in renal cortex in streptozotocin-induced diabetic rats are significantly increased; UⅡat certain concentrations can promote the proliferation and DNA synthesis of mesangial cells, and increase the secretion and mRNA expression of FN, ColⅣ, TGF-β1 and AngⅡ(AT_1). The findings suggest that UⅡmay directly or indirectly participate in the development and progression of diabetic nephropathy.
引文
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