12-脂氧化酶对糖尿病肾病鼠肾小球p27~（kip1）表达的影响及机制研究
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摘要
糖尿病肾病(DN)已逐渐成为威胁人类健康的重要疾病。探讨其发病机制,确定其有效的治疗方法是目前需要解决的问题。DN的特征性病变是肾小球肥大和细胞外基质(ECM)积聚。DN时,12-脂氧化酶(12-LO)能够通过其代谢产物引起肾小球ECM积聚。然而,12-LO是否参与肾小球细胞肥大的病理过程,目前尚无研究。细胞周期素激酶抑制剂(CKI) p27kip1的表达变化与DN时肾小球细胞肥大的发生密切相关。DN时12-LO代谢途径与CKI表达调节及肾小球细胞肥大的关系尚不清楚。
本研究采用细胞培养、STZ诱导糖尿病动物模型的方法,应用形态学、免疫组织化学、ELISA、Western blot等方法探讨12-LO是否通过p38 MAPK通路导致细胞肥大、观察12-LO在DN时细胞肥大中的作用。
研究结果表明：通过抑制p38 MAPK活性可有效地阻断12(S)-HETE诱导的系膜细胞(MC)内p27kip1的表达,而12(S)-HETE对内参照p38 MAPK和β-actin无明显影响。12-LO抑制剂CDC可抑制2型糖尿病大鼠肾小球体积增大,降低尿白蛋白；阻止肾小球内p38 MAPK活性和p27kiPi蛋白表达增加。野生型糖尿病小鼠与12-LO基因敲除糖尿病小鼠相比,p38 MAPK活性、p27kipi蛋白表达及ECM积聚在肾小球内增高。表明12-LO通过p38 MAPK通路上调糖尿病肾小球内p27kipi的表达而引起肾小球肥大,此结果为临床上将12-LO作为新的治疗靶点来延缓DN的进展提供新的方向和理论依据。
本研究创新之处：1)以CKI的表达变化作为DN时反映肾小球肥大的标志,利用体外模型(细胞培养)和体内模型,探讨12-LO/p38 MAPK通路对肾小球细胞和肾小球内CKI表达的影响。2)采用高脂饮食结合小剂量STZ诱导的2型糖尿病动物模型来探讨抑制12-LO对肾小球内CKI的影响,完善12-LO在以肾小球细胞肥大和ECM积聚为特征性病变的DN进展中的作用,并阐明通过抑制12-LO来延缓DN的进展的重要
Early pathological changes of diabetic nephropathy is manifested mainly glomerular hypertrophy, and the emergence of extracellular matrix (ECM) increasing. With the lesions progressing, glomerular sclerosis and renal interstitial fibrosis gradually arise, culminating in renal failure. Diabetic nephropathy is the result of many factors and high blood sugar is a prerequisite for kidney damage occurring. Sorbitol metabolism, deposition of advanced glycation end products, protein kinase C activation, hexose amine pathways metabolic abnormalities and RAS activation caused by high blood sugar are the main pathogenesis of diabetic nephropathy, other causes, including genetic factors, renal hemodynamic abnormalities, high blood pressure in diabetic nephropathy may play an important role in the development process. In recent years,12-lipoxygenase and cell cycle regulatory proteins in the pathogenesis of diabetic nephropathy had been increased attention and devoted to become a research hotspot.
Lipoxygenase (lipoxygenase,LO) is a polyunsaturated fatty acid oxygenase. LO in mammals according to the similarity of its isomerase genotype were divided into white blood cell types, epithelial cell type and platelet type. Cell membrane phospholipids by the activation of phospholipase A2-catalyzed release of arachidonic acid (Arachidonic acid:AA). LO isomerase with a specific location by adding oxygen molecules can be divided into 5-,8-,12-,15-LO isomerase, to the corresponding Hydroxyeicosatetraenoic acid (HETE) with AA as a substrate generates. Study confirmed that atherosclerosis, hypertension, diabetes and other serious diseases that affect human health have close relationship with the leukocyte-type 12-LO expression. Studies have shown that the key enzyme-12-LO gene and protein levels with arachidonic acid (AA) metabolism, not only increase the expression in glomerular mesangial cells, podocyte and diabetes model (type 1 and type 2) renal by high glucose-stimulated, but also its role are similar with TGF-βand Ang□, and thus that it is regarded as a new key factor closely related to the progress of DN. Studies have shown that 12-LO can also cause glomerular ECM accumulation. The above studies have shown that 12-LO play an important role in the promotion of the occurrence and development of DN in the pathology. However, Could 12-LO give rise to glomerular hypertrophy, there were no relevant reports.
hypertrophy cells have the character of increasing in cyclin kinase inhibitor (CKI) expression and intracellular protein synthesis and so on. All causes of kidney damage can be expressed as cell proliferation, apoptosis and cell hypertrophy, and these changes are related to the regulation of cell cycle abnormalities. Study confirmed that in DN, there are some cells proliferation occurring such as renal interstitial cell, but most of kidney cells, especially mesangial cells and renal tubular epithelial cells cause cell hypertrophy in stagnation of the the late G1 after activation of the Go period, which is characteristic of early diabetic nephropathy change, and it is different from a variety of other primary or secondary renal diseases characterized by cell cycle. Studies have shown that mesangial cells (MC) cultured by high glucose showed a short-lived transient cell proliferation, and then G1/S cell cycle escaping.Its DNA synthesis was inhibited while the protein and RNA synthesis increased, the increase in intracellular protein content were out of proportion with the DNA synthesis, cell growth was arrested in the G1 phase, which caused the increase of cell volume, leading to the occurrence of cell hypertrophy. The cell cycle is mainly controlled by the positive and negative cell cycle regulatory proteins. Cell cycle positive regulated proteins include cyclin and CDK, activity can only be obtained when the two proteins are combined into compound. Experiments show that diabetic glomerular hypertrophy is closely related to the occurrence and CKI, but not with the level of cyclin and CDK. Cyclin kinase inhibitor (CKI) is a negative regulator of cell cycle proteins, presenting in the nucleus, and closely combined with Cyclin-CDK complexes, inhibiting CDK activity, affecting the function of the downstream target proteins, thereby preventing conversion of G1/S and G2/M, leading to cell cycle arrest, inhibiting cell cycle operation. If the cell cycle arrest in late G1,cell hypertrophy will occur. CKI is divided into two family of INK and CIP/KIP. Research has clearly showed that CIP/KIP family proteins such as p21waf1, p27kipl, p57kip2 can inhibit a variety of, CDK activity by combining with it, which is the key factors leading to cell cycle escape and causing cell hypertrophy. In diabetic conditions, increases in p21waf1, p27kipl expression are related to renal cell hypertrophy and glomerular hypertrophy. p27kipl is a non-specific negative control of cell cycle proteins, can inhibit a number of different CDK complexes, which cause that the cell can not pass G1 phase, leading to cell hypertrophy. In normal resting state, p27kipl in the three kinds of glomerular intrinsic cells has a very strong expression of the structural expression, it play an important role in cell cycle regulation of glomerular disease, and it is a major factor in inducing cell hypertrophy. The level of p27kipl protein vary in the cell cycle, it reach the highest in quiescent (Go) and G1 phase, while it begin to decline in the transition from G1 phase to S phase and then the cells start to divide and hyperplasia. p27kip1 is necessary for the maintaining the quiescent state of cells. The expression and regulation of p27kipl is multi-faceted.The study shows the regulation and expression of p27kipl mostly occurs in post-transcriptional levels, including protein translation, protein degradation and phosphorylation levels of modification, while not at the transcriptional level. The degradation of p27kipl achieve mainly through the ubiquitin/proteasome pathway. Positioning of p27kipl in the cell has also a certain effect on its function into full play and degradation. Because the function of inhibiting CDK and degradation of p27kipl in G1 phase were done in entering into the nucleus, the intracellular location of abnormalities can also affect the expression and physiological function of p27kipl.
Recent studies have showed that p21wafl, p27kipl are not only closely related to cell hypertrophy, but also to cell aging. A common feature of diabetic nephropathy and aging kidney possess is renal cell hypertrophy. In vitro experiments show that p21wafl, p27kip1 increased the expression in the elderly mesangial cells comparied with the younger glomerular mesangial cells, but the in vivo experiments show that only the glomerular p27kipl expression increased in the elderly glomeruli compared with young, there is no change of p21wafl expression in glomeruli in the elderly, its mechanism is unclear. Thus, p27kipl is landmark proteins which associated both diabetes and aging of glomerular mesangial cells with glomerular hypertrophy in the CIP/KIP family proteins. p27kipl is not only a sign of cell hypertrophy and aging, but also main functions of proteins promoting cell hypertrophy and senescence.
Research Methods 1) Observe the mesangial cell p27kipl protein expression under 12-LO product 12 (S)-HETE (10"7mmol/L) stimulation with or without p38 MAPK(p38 MAPK) inhibitor (SB203580, 1umol/L) and investigate whether 12-LO induce p27kipl protein expression through p38 MAPK pathway.2) Investigate the role of 12-LO in the glomerular hypertrophy using STZ-induced diabetic animal model. Male SD rats were divided into normal diet control group, normal diet+12-LO inhibitor (CDC,8mg/kg,3 times /week, subcutaneously) treatment group, high-fat diet low-dose streptozotocin (STZ 35mg/kg, intraperitoneal injection)-induced type 2 diabetes group, high-fat diet with low-dose STZ-induced type 2 diabetes+CDC treatment group, continuous subcutaneous injunction CDC for 1 months. The wild-type and 12-LO gene knockout C57BL/6 mice were randomly divided into wild-type control group,12-LO gene knockout group, wild-type STZ-induced type 1 diabetic group,12-LO gene knock-STZ-induced type 1 diabetic group, feeding for 16 weeks. Collect urine, blood and extract the kidney, and then glomeruli were isolated with the series of sifting after the end of the experiment. Detect the target protein changes by Western blot and immunohistochemistry.
The results of this study are as follows:
1) It is effective to block expression of p27kipl in mesangial cell induced by 12 (S)-HETE through inhibiting p38MAPK activity, the difference was statistically significant (P <0.01).
2) CDC can decrease type 2 diabetic rats glomerular volume and reduce urinary albumin excretion(P<0.01).
3) CDC can significantly decrease glomerular p38 MAPK activity and p27kip1 protein expression, compared with CDC untreated diabetic rats (P<0.01).
4) Compared with 12-LO knock-out diabetic mice, p38 MAPK activity, p27kip1 protein expression and ECM accumulation increased in the glomeruli in wild-type diabetic mice, the difference was statistically significant (P<0.01).
From this study,we can draw the following conclusions:
1) 12-LO can induce p27kipl protein expression through p38 MAPK pathway.
2) 12-LO inhibition not only reduce urinary albumin excretion and glomerular volume,but also decrease glomerular p38 MAPK activation and p27kipl protein expression under diabetic conditions.
In summary,12-LO induces glomerular p27kipl expression through the p38 MAPK pathway in diabetic conditions.
本研究采用细胞培养、STZ诱导糖尿病动物模型的方法,应用形态学、免疫组织化学、ELISA、Western blot等方法探讨12-LO是否通过p38 MAPK通路导致细胞肥大、观察12-LO在DN时细胞肥大中的作用。
研究结果表明：通过抑制p38 MAPK活性可有效地阻断12(S)-HETE诱导的系膜细胞(MC)内p27kip1的表达,而12(S)-HETE对内参照p38 MAPK和β-actin无明显影响。12-LO抑制剂CDC可抑制2型糖尿病大鼠肾小球体积增大,降低尿白蛋白；阻止肾小球内p38 MAPK活性和p27kiPi蛋白表达增加。野生型糖尿病小鼠与12-LO基因敲除糖尿病小鼠相比,p38 MAPK活性、p27kipi蛋白表达及ECM积聚在肾小球内增高。表明12-LO通过p38 MAPK通路上调糖尿病肾小球内p27kipi的表达而引起肾小球肥大,此结果为临床上将12-LO作为新的治疗靶点来延缓DN的进展提供新的方向和理论依据。
本研究创新之处：1)以CKI的表达变化作为DN时反映肾小球肥大的标志,利用体外模型(细胞培养)和体内模型,探讨12-LO/p38 MAPK通路对肾小球细胞和肾小球内CKI表达的影响。2)采用高脂饮食结合小剂量STZ诱导的2型糖尿病动物模型来探讨抑制12-LO对肾小球内CKI的影响,完善12-LO在以肾小球细胞肥大和ECM积聚为特征性病变的DN进展中的作用,并阐明通过抑制12-LO来延缓DN的进展的重要
Early pathological changes of diabetic nephropathy is manifested mainly glomerular hypertrophy, and the emergence of extracellular matrix (ECM) increasing. With the lesions progressing, glomerular sclerosis and renal interstitial fibrosis gradually arise, culminating in renal failure. Diabetic nephropathy is the result of many factors and high blood sugar is a prerequisite for kidney damage occurring. Sorbitol metabolism, deposition of advanced glycation end products, protein kinase C activation, hexose amine pathways metabolic abnormalities and RAS activation caused by high blood sugar are the main pathogenesis of diabetic nephropathy, other causes, including genetic factors, renal hemodynamic abnormalities, high blood pressure in diabetic nephropathy may play an important role in the development process. In recent years,12-lipoxygenase and cell cycle regulatory proteins in the pathogenesis of diabetic nephropathy had been increased attention and devoted to become a research hotspot.
Lipoxygenase (lipoxygenase,LO) is a polyunsaturated fatty acid oxygenase. LO in mammals according to the similarity of its isomerase genotype were divided into white blood cell types, epithelial cell type and platelet type. Cell membrane phospholipids by the activation of phospholipase A2-catalyzed release of arachidonic acid (Arachidonic acid:AA). LO isomerase with a specific location by adding oxygen molecules can be divided into 5-,8-,12-,15-LO isomerase, to the corresponding Hydroxyeicosatetraenoic acid (HETE) with AA as a substrate generates. Study confirmed that atherosclerosis, hypertension, diabetes and other serious diseases that affect human health have close relationship with the leukocyte-type 12-LO expression. Studies have shown that the key enzyme-12-LO gene and protein levels with arachidonic acid (AA) metabolism, not only increase the expression in glomerular mesangial cells, podocyte and diabetes model (type 1 and type 2) renal by high glucose-stimulated, but also its role are similar with TGF-βand Ang□, and thus that it is regarded as a new key factor closely related to the progress of DN. Studies have shown that 12-LO can also cause glomerular ECM accumulation. The above studies have shown that 12-LO play an important role in the promotion of the occurrence and development of DN in the pathology. However, Could 12-LO give rise to glomerular hypertrophy, there were no relevant reports.
hypertrophy cells have the character of increasing in cyclin kinase inhibitor (CKI) expression and intracellular protein synthesis and so on. All causes of kidney damage can be expressed as cell proliferation, apoptosis and cell hypertrophy, and these changes are related to the regulation of cell cycle abnormalities. Study confirmed that in DN, there are some cells proliferation occurring such as renal interstitial cell, but most of kidney cells, especially mesangial cells and renal tubular epithelial cells cause cell hypertrophy in stagnation of the the late G1 after activation of the Go period, which is characteristic of early diabetic nephropathy change, and it is different from a variety of other primary or secondary renal diseases characterized by cell cycle. Studies have shown that mesangial cells (MC) cultured by high glucose showed a short-lived transient cell proliferation, and then G1/S cell cycle escaping.Its DNA synthesis was inhibited while the protein and RNA synthesis increased, the increase in intracellular protein content were out of proportion with the DNA synthesis, cell growth was arrested in the G1 phase, which caused the increase of cell volume, leading to the occurrence of cell hypertrophy. The cell cycle is mainly controlled by the positive and negative cell cycle regulatory proteins. Cell cycle positive regulated proteins include cyclin and CDK, activity can only be obtained when the two proteins are combined into compound. Experiments show that diabetic glomerular hypertrophy is closely related to the occurrence and CKI, but not with the level of cyclin and CDK. Cyclin kinase inhibitor (CKI) is a negative regulator of cell cycle proteins, presenting in the nucleus, and closely combined with Cyclin-CDK complexes, inhibiting CDK activity, affecting the function of the downstream target proteins, thereby preventing conversion of G1/S and G2/M, leading to cell cycle arrest, inhibiting cell cycle operation. If the cell cycle arrest in late G1,cell hypertrophy will occur. CKI is divided into two family of INK and CIP/KIP. Research has clearly showed that CIP/KIP family proteins such as p21waf1, p27kipl, p57kip2 can inhibit a variety of, CDK activity by combining with it, which is the key factors leading to cell cycle escape and causing cell hypertrophy. In diabetic conditions, increases in p21waf1, p27kipl expression are related to renal cell hypertrophy and glomerular hypertrophy. p27kipl is a non-specific negative control of cell cycle proteins, can inhibit a number of different CDK complexes, which cause that the cell can not pass G1 phase, leading to cell hypertrophy. In normal resting state, p27kipl in the three kinds of glomerular intrinsic cells has a very strong expression of the structural expression, it play an important role in cell cycle regulation of glomerular disease, and it is a major factor in inducing cell hypertrophy. The level of p27kipl protein vary in the cell cycle, it reach the highest in quiescent (Go) and G1 phase, while it begin to decline in the transition from G1 phase to S phase and then the cells start to divide and hyperplasia. p27kip1 is necessary for the maintaining the quiescent state of cells. The expression and regulation of p27kipl is multi-faceted.The study shows the regulation and expression of p27kipl mostly occurs in post-transcriptional levels, including protein translation, protein degradation and phosphorylation levels of modification, while not at the transcriptional level. The degradation of p27kipl achieve mainly through the ubiquitin/proteasome pathway. Positioning of p27kipl in the cell has also a certain effect on its function into full play and degradation. Because the function of inhibiting CDK and degradation of p27kipl in G1 phase were done in entering into the nucleus, the intracellular location of abnormalities can also affect the expression and physiological function of p27kipl.
Recent studies have showed that p21wafl, p27kipl are not only closely related to cell hypertrophy, but also to cell aging. A common feature of diabetic nephropathy and aging kidney possess is renal cell hypertrophy. In vitro experiments show that p21wafl, p27kip1 increased the expression in the elderly mesangial cells comparied with the younger glomerular mesangial cells, but the in vivo experiments show that only the glomerular p27kipl expression increased in the elderly glomeruli compared with young, there is no change of p21wafl expression in glomeruli in the elderly, its mechanism is unclear. Thus, p27kipl is landmark proteins which associated both diabetes and aging of glomerular mesangial cells with glomerular hypertrophy in the CIP/KIP family proteins. p27kipl is not only a sign of cell hypertrophy and aging, but also main functions of proteins promoting cell hypertrophy and senescence.
Research Methods 1) Observe the mesangial cell p27kipl protein expression under 12-LO product 12 (S)-HETE (10"7mmol/L) stimulation with or without p38 MAPK(p38 MAPK) inhibitor (SB203580, 1umol/L) and investigate whether 12-LO induce p27kipl protein expression through p38 MAPK pathway.2) Investigate the role of 12-LO in the glomerular hypertrophy using STZ-induced diabetic animal model. Male SD rats were divided into normal diet control group, normal diet+12-LO inhibitor (CDC,8mg/kg,3 times /week, subcutaneously) treatment group, high-fat diet low-dose streptozotocin (STZ 35mg/kg, intraperitoneal injection)-induced type 2 diabetes group, high-fat diet with low-dose STZ-induced type 2 diabetes+CDC treatment group, continuous subcutaneous injunction CDC for 1 months. The wild-type and 12-LO gene knockout C57BL/6 mice were randomly divided into wild-type control group,12-LO gene knockout group, wild-type STZ-induced type 1 diabetic group,12-LO gene knock-STZ-induced type 1 diabetic group, feeding for 16 weeks. Collect urine, blood and extract the kidney, and then glomeruli were isolated with the series of sifting after the end of the experiment. Detect the target protein changes by Western blot and immunohistochemistry.
The results of this study are as follows:
1) It is effective to block expression of p27kipl in mesangial cell induced by 12 (S)-HETE through inhibiting p38MAPK activity, the difference was statistically significant (P <0.01).
2) CDC can decrease type 2 diabetic rats glomerular volume and reduce urinary albumin excretion(P<0.01).
3) CDC can significantly decrease glomerular p38 MAPK activity and p27kip1 protein expression, compared with CDC untreated diabetic rats (P<0.01).
4) Compared with 12-LO knock-out diabetic mice, p38 MAPK activity, p27kip1 protein expression and ECM accumulation increased in the glomeruli in wild-type diabetic mice, the difference was statistically significant (P<0.01).
From this study,we can draw the following conclusions:
1) 12-LO can induce p27kipl protein expression through p38 MAPK pathway.
2) 12-LO inhibition not only reduce urinary albumin excretion and glomerular volume,but also decrease glomerular p38 MAPK activation and p27kipl protein expression under diabetic conditions.
In summary,12-LO induces glomerular p27kipl expression through the p38 MAPK pathway in diabetic conditions.
引文
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