CNP-NPR-B-cGMP信號(hào)通路在腎缺血再灌注損傷中的作用
發(fā)布時(shí)間：2018-10-11 08:22
【摘要】：腎缺血再灌注損傷(ischemia reperfusion injury, IRI)是腎組織缺血時(shí)和其后恢復(fù)血液灌注時(shí)器官功能不能恢復(fù)正常,甚至發(fā)生更為嚴(yán)重的組織損傷或器官功能衰竭。腎臟由于其組織結(jié)構(gòu)和功能的特殊性,對(duì)缺血再灌注損傷特別敏感,臨床上常見因缺血引起急性腎功能衰竭(acute renal failue, ARF)的發(fā)生,如急性缺血性腎功衰竭、心肺復(fù)蘇、心臟體外循環(huán)、失血性休克、嚴(yán)重脫水、彌散性血管內(nèi)凝血、心臟手術(shù)及腎臟移植術(shù)等過程中,特別是多器官功能衰竭的危重患者幾乎都伴有ARF的發(fā)生。盡管進(jìn)行積極的對(duì)癥支持治療,但還是出現(xiàn)很高的發(fā)病率和死亡率。實(shí)驗(yàn)證明,心房鈉尿肽(atrial natriuretic peptide, ANP)可有效地減輕心臟、肝臟及胃等器官的缺血再灌注損傷,起明顯的保護(hù)作用。近年來研究表明,ANP對(duì)大鼠腎缺血再灌注損傷也具有保護(hù)作用,其保護(hù)作用是增加腎小球?yàn)V過率(glomerular filtration rate, GFR)和腎髓質(zhì)的血流量,減輕髓質(zhì)部生成表皮生長因子(epithelial growth factor, EGF)細(xì)胞的損傷,恢復(fù)腎小管上皮細(xì)胞的完整性；ANP可減輕中性白細(xì)胞的活性,抑制其釋放各種炎癥介質(zhì)和氧自由基的生成保護(hù)腎功能,但其作用機(jī)制尚不清楚。 鈉尿肽(natriuretic peptides, NPs)是新發(fā)現(xiàn)的肽類激素,主要有ANP、腦鈉尿肽(brain natriuretic peptide, BNP)及C-型鈉尿肽(C-type natriuretic peptide,CNP)等,其共有的效應(yīng)是利尿、排鈉、舒張血管、降低血壓和調(diào)節(jié)水電解質(zhì)平衡。ANP和BNP主要由心臟合成和分泌,而CNP主要由內(nèi)皮細(xì)胞分泌,是腦或神經(jīng)系統(tǒng)特異性表達(dá)的神經(jīng)遞質(zhì)。現(xiàn)已確認(rèn)能與鈉尿肽結(jié)合的受體有三種亞型：A型鈉尿肽受體(natriuretic peptide receptor type A, NPR-A)、B型鈉尿肽受體(natriuretic peptide receptor type B, NPR-B)及清除型鈉尿肽受體(natriuretic peptide clearance receptor, NPR-C)。ANP和BNP主要與NPR-A結(jié)合,CNP則主要與NPR-B結(jié)合而發(fā)揮其生物學(xué)效應(yīng)。研究表明,鈉尿肽及其受體廣泛分布在腎臟,但是NPs-NPR-cGMP系統(tǒng)在腎缺血再灌注的病理生理學(xué)作用尚不甚清楚。 為此,本研究從形態(tài)學(xué)和分子生物學(xué)等角度觀察和探討CNP-NPR-B-cGMP信號(hào)通路在腎缺血再灌注損傷中的作用及其機(jī)制。 本研究利用大鼠腎缺血再灌注模型,制備血清樣本測定肌酐(creatinine, Cr)、尿素氮(blood urine nitrogen, BUN)等腎功能指標(biāo),且利用光鏡和電鏡觀察腎組織形態(tài)學(xué)及腎組織超微結(jié)構(gòu),利用放射免疫分析和酶聯(lián)免疫法測定血清CNP濃度,采用RT-PCR和免疫組織化學(xué)方法觀察CNP及NPR-B mRNA的表達(dá)和分布。另外,取24只SD大鼠隨機(jī)分為假手術(shù)組(sham)、腎缺血再灌注組(ischemia reperfusion, IR)及腎缺血再灌注即時(shí)CNP給藥組(IR+CNP)(每組8只),測定血清Cr、BUN及腎組織SOD活性及MDA含量,且利用光鏡觀察腎組織形態(tài)學(xué)變化和采用免疫印跡技術(shù)觀察腎組織Bax、Bcl-2的表達(dá)變化。 實(shí)驗(yàn)結(jié)果如下： 1.大鼠腎缺血再灌注組血清Cr、BUN水平且明顯高于假手術(shù)組(n=8,P0.01),并呈現(xiàn)時(shí)間依賴性特征。 2.假手術(shù)組腎臟組織結(jié)構(gòu)清楚,腎小管上皮細(xì)胞完整,只有輕度炎性細(xì)胞浸潤；IR組肉眼觀察可見腎臟體積明顯增大而質(zhì)軟,剖面見腎髓質(zhì)呈暗紅色；皮質(zhì)腫脹而蒼白。顯微鏡下觀察,IR組近端腎小管上皮細(xì)胞空泡及顆粒變性,細(xì)胞扁平,管腔擴(kuò)張,刷狀緣脫落消失,管腔內(nèi)有脫落的上皮、管型和炎癥滲出物；基底膜裸露,甚至呈現(xiàn)腎小管細(xì)胞的節(jié)段性灶狀壞死。腎小管間質(zhì)有不同程度的炎癥細(xì)胞浸潤和水腫。遠(yuǎn)端腎小管和集合管管腔內(nèi)可見細(xì)胞碎片或顆粒管型,腎小管基底膜節(jié)段性斷裂,斷裂部位可見淋巴細(xì)胞、單核細(xì)胞及中性粒細(xì)胞浸潤,腎間質(zhì)彌漫并水腫。sham組電鏡下超微結(jié)構(gòu)基本正常,線粒體嵴完整,未見腫脹,粗面內(nèi)質(zhì)網(wǎng)結(jié)構(gòu)完整,排列整齊；IR組電鏡下可見腎小管上皮細(xì)胞微絨毛脫落,線粒體腫脹、線粒體嵴消失,內(nèi)質(zhì)網(wǎng)擴(kuò)張,初級(jí)和次級(jí)溶酶體增多,吞噬空胞亦可見有增多現(xiàn)象。甚至上皮細(xì)胞崩解脫落,僅可見裸露或斷裂的基底膜。 3.假手術(shù)組及缺血再灌注組不同時(shí)間段(0/1/2/4h)血清CNP含量無明顯差異(n=8,P0.05)。 4.缺血再灌注組腎組織CNP mRNA表達(dá)明顯上調(diào),且在再灌注2 hour時(shí)表達(dá)最高(n=8,P0.05)。 5.假手術(shù)組及缺血再灌注組腎組織NPR-B均呈陽性,可見到散在分布的棕色顆粒,但與假手術(shù)組相比再灌注組呈陽性的棕色顆粒明顯增多,染色明顯加深。另外,缺血再灌注組大鼠腎組織中NPR-B mRNA表達(dá)明顯高于正常對(duì)照組。 6.假手術(shù)組腎臟組織結(jié)構(gòu)清楚,腎小管上皮細(xì)胞完整,只有輕度炎性細(xì)胞浸潤；再灌注組腎臟體積明顯增大而質(zhì)軟,剖面見腎髓質(zhì)呈暗紅色；皮質(zhì)腫脹而蒼白。顯微鏡下近端腎小管上皮細(xì)胞空泡及顆粒變性,細(xì)胞扁平,管腔擴(kuò)張,刷狀緣脫落消失,管腔內(nèi)有脫落的上皮、管型和炎癥滲出物,基底膜裸露,甚至可見腎小管細(xì)胞的節(jié)段性灶狀壞死。腎小管間質(zhì)可有不同程度的炎癥細(xì)胞浸潤和水腫,遠(yuǎn)端腎小管和集合管管腔內(nèi)可見細(xì)胞碎片或顆粒管型。腎小管基底膜節(jié)段性斷裂,斷裂部位可見淋巴細(xì)胞、單核細(xì)胞及中性粒細(xì)胞浸潤,腎間質(zhì)彌漫水腫。腎小球和腎小動(dòng)脈未見明顯改變。CNP組腎小管排列基本正常,以腫脹為主,腎間質(zhì)水腫、充血,炎性細(xì)胞浸潤不明顯。 7.缺血再灌注組24小時(shí)后血清Cr、BUN水平明顯高于假手術(shù)組(n=8,P0.001);CNP即時(shí)給藥組較缺血再灌注組明顯下降(n=8,P0.05)。 8.缺血再灌注組與假手術(shù)組相比MDA含量顯著升高,SOD活性顯著下降(n=8,P0.01和P0.05)；CNP即時(shí)給藥組與IR組相比MDA含量明顯減少,SOD活性有所提高(n=8,P0.01和P0.05)。 9.與假手術(shù)組及CNP即時(shí)給藥組相比,缺血再灌注組腎組織Bax表達(dá)明顯增加(n=8,P0.05),而Bcl-2的表達(dá)在3組之間無明顯差異,但是CNP即時(shí)給藥組Bax/Bcl-2比值降低(n=8,P0.05)。 以上結(jié)果提示： 1.腎缺血再灌注時(shí)組織結(jié)構(gòu)和功能明顯受到損傷,尤其在皮髓交界區(qū)和髓質(zhì)部位。 2.腎缺血再灌注損傷時(shí)腎組織CNP及NPR-B的表達(dá)明顯上調(diào)。 3.CNP明顯改善缺血再灌注損傷的腎臟組織結(jié)構(gòu)和功能,呈現(xiàn)抗損傷作用。 4.CNP對(duì)損傷的腎組織具有明顯的抗氧化作用。 5.CNP對(duì)缺血再灌注腎具有明顯的抗細(xì)胞凋亡效應(yīng),其作用是通過上調(diào)抗凋亡基因表達(dá)的途徑實(shí)現(xiàn)的。
[Abstract]:Renal ischemia-reperfusion injury (IRI) is the function of organ failure in renal tissue ischemia and later recovery of blood perfusion, and even more serious tissue injury or organ failure. Due to the particularity of its structure and function, the kidney is particularly sensitive to ischemia-reperfusion injury. In clinic, acute renal failure caused by ischemia, such as acute ischemic renal failure, cardiopulmonary resuscitation, cardiopulmonary bypass, hemorrhagic shock, Severe dehydration, disseminated intravascular coagulation, cardiac surgery, and kidney transplantation, especially in critically ill patients with multiple organ failure, are almost accompanied by the occurrence of death. Despite positive symptomatic support, there was still a high incidence of morbidity and mortality. The experimental results show that atrial natriuretic peptide (ANP) can effectively reduce the ischemia-reperfusion injury of heart, liver and stomach. Recent studies have shown that ANP has a protective effect on renal ischemia-reperfusion injury in rats, and its protective effect is to increase the glomerular filtration rate (GFR) and the blood flow of renal medulla, and to reduce the damage of epidermal growth factor (EGF) cells in medulla. To restore the integrity of renal tubular epithelial cells, ANP can reduce the activity of neutrophils and inhibit the release of various inflammatory mediators and oxygen free radicals to protect renal function, but its mechanism of action is not clear. The natriuretic peptide (NPs) is a newly discovered peptide hormone, mainly including ANP, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The common effect is diuretic, sodium excretion, vasodilation, blood pressure reduction and water electrolyte regulation. The balance. ANP and BNP are mainly synthesized and secreted by the heart, while CNP is mainly secreted by endothelial cells, which is the nerve specifically expressed by the brain or nervous system. It has been recognized that there are three subtypes of receptors capable of binding to natriuretic peptide: Atype natriuretic peptide receptor type A (NPR-A), type B natriuretic peptide receptor type B (NPR-B) and clear natriuretic peptide receptor (NPR-C). ANP and BNP are mainly combined with NPR-A, and CNP is mainly combined with NPR-B to exert its biology. The results show that the natriuretic peptide and its receptors are widely distributed in the kidney, but the pathophysiological role of NPs-NPR-cGMP system in renal ischemia-reperfusion is not very important. To this end, we observed and discussed the effect of CNP-NPR-B-cGMP signal pathway in renal ischemia-reperfusion injury from the aspects of morphology and molecular biology. Using the model of renal ischemia-reperfusion in rats, serum samples were prepared to determine renal function indices such as creatidine, Cr, blood urine, and so on, and renal tissue morphology was observed by light microscope and electron microscope. The concentrations of CNP and NPR-B mR were observed by RT-PCR and immunohistochemistry. In addition, 24 SD rats were randomly divided into sham operation group (sham), renal ischemia reperfusion group (IR) and renal ischemia-reperfusion instant CNP administration group (IR + CNP) (8 rats in each group). Serum Cr, NPY and SOD in renal tissues were determined. The activity and MDA content were observed, and the morphological changes of renal tissues were observed by light microscope and the expression of Bax and Bc in renal tissues were observed by western blot technique. expression change of l-2 The results of the experiment were as follows: 1. The levels of serum Cr and NPY in renal ischemic reperfusion group were significantly higher than that in sham operation group (n = 8, P <0.01). 01) Time-dependent characteristics were presented and time-dependent characteristics were presented. 2. The renal tissue structure of the sham-operated group was clear, the renal tubular epithelial cells were intact, only mild inflammatory cell infiltration was observed. It was seen that the renal medulla was dark red; the cortex was swollen and pale. Under the microscope, the vacuoles and degeneration of the proximal tubular epithelial cells of the IR group were observed, the cells were flat, the lumen of the tube was expanded, the brush-like margin disappeared, and the epithelial, tubular and inflammatory exudates were removed in the lumen of the tube. The basement membrane was exposed. Even the segmental focal necrosis of the renal tubular cells. There is a different degree of inflammatory cell infiltration and edema in the stroma. The distal tubules and the lumen of the collection tube are visible cell debris or particle casts, tubular basement membrane segment fracture, fracture site visible lymphocytes, monocytes Neutrophil infiltration, renal interstitial diffusion and edema were observed. The ultrastructures under electron microscope of sham group were basically normal, the mitochondria were intact, swelling was not observed, the structure of rough reticulum was complete, the arrangement was orderly, and the microvilli of renal tubular epithelial cells showed off in the IR group under electron microscope. Swelling of granule, disappearance of mitochondrial membrane, dilatation of ER, primary and secondary dissolution There is an increase in the number of enzymes, and an increase in the number of cells can be seen. Even the epithelial cells Disintegration, only visible or broken basal membrane. 3. sham operation group and ischemia-reperfusion group for different time periods (0/ 1/ 2/ 4h) serum C There was no significant difference in NP content (n = 8, P0.05). The expression of NPR-B was highest (n = 8, P 0.05). 5. Both the sham operation group and the renal tissue NPR-B of the ischemia-reperfusion group were positive. Compared with the reperfusion group, the positive brown granules increased significantly, and the staining was significantly increased. The expression of NPR-B mRNA in renal tissues of rats was significantly higher than that in normal control group. The dirty volume is obviously increased and the quality is soft; the section is seen in the medulla of the kidney; the renal medulla is dark red; the cortex is swollen and pale. The near-end tubular epithelial cell vacuoles and particle degeneration under the microscope, the cell is flat, the tube cavity is expanded, the brush-like edge falls off, and the exfoliated epithelium, the tube and the tube cavity are formed in the tube cavity. Inflammatory exudate, bare basement membrane, and even segmental focal necrosis of tubular cells. Renal tubular stroma can have varying degrees of inflammatory cells. Infiltration and edema, visible cell debris or particle casts in the distal tubules and manifold lumen. Tubular basement membrane segment fracture, fracture Site visible lymphocytes, monocytes, and neutralizing Neutrophil infiltration, renal interstitial diffuse edema. No significant changes in glomerular and renal function were found. Renal tubular arrangement of CNP group After 24 hours of ischemia-reperfusion group, the level of serum Cr and NPY was significantly higher than that of sham-operated group (n = 8, P0.001). (n = 8, P0.05). Compared with the sham operation group, the content of MDA increased significantly and the activity of SOD decreased significantly (n = 8, P0.01 and P0.05). Compared with sham operation group and CNP, the expression of Bax was significantly increased (n = 8, P0.05). Significant differences, but C The ratio of Bax/ Bcl-2 decreased (n = 8, P0.05). Results: 1. The structure and function of tissue were obviously damaged during renal ischemia-reperfusion. especially at the junctional region and medulla of the skin. The expression of NPR-B was obviously up-regulated. To improve the structure and function of kidney tissue damaged by ischemia-reperfusion injury, and present an anti-injury effect.
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類號(hào)】：R363
本文編號(hào)：2263501
[Abstract]:Renal ischemia-reperfusion injury (IRI) is the function of organ failure in renal tissue ischemia and later recovery of blood perfusion, and even more serious tissue injury or organ failure. Due to the particularity of its structure and function, the kidney is particularly sensitive to ischemia-reperfusion injury. In clinic, acute renal failure caused by ischemia, such as acute ischemic renal failure, cardiopulmonary resuscitation, cardiopulmonary bypass, hemorrhagic shock, Severe dehydration, disseminated intravascular coagulation, cardiac surgery, and kidney transplantation, especially in critically ill patients with multiple organ failure, are almost accompanied by the occurrence of death. Despite positive symptomatic support, there was still a high incidence of morbidity and mortality. The experimental results show that atrial natriuretic peptide (ANP) can effectively reduce the ischemia-reperfusion injury of heart, liver and stomach. Recent studies have shown that ANP has a protective effect on renal ischemia-reperfusion injury in rats, and its protective effect is to increase the glomerular filtration rate (GFR) and the blood flow of renal medulla, and to reduce the damage of epidermal growth factor (EGF) cells in medulla. To restore the integrity of renal tubular epithelial cells, ANP can reduce the activity of neutrophils and inhibit the release of various inflammatory mediators and oxygen free radicals to protect renal function, but its mechanism of action is not clear. The natriuretic peptide (NPs) is a newly discovered peptide hormone, mainly including ANP, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The common effect is diuretic, sodium excretion, vasodilation, blood pressure reduction and water electrolyte regulation. The balance. ANP and BNP are mainly synthesized and secreted by the heart, while CNP is mainly secreted by endothelial cells, which is the nerve specifically expressed by the brain or nervous system. It has been recognized that there are three subtypes of receptors capable of binding to natriuretic peptide: Atype natriuretic peptide receptor type A (NPR-A), type B natriuretic peptide receptor type B (NPR-B) and clear natriuretic peptide receptor (NPR-C). ANP and BNP are mainly combined with NPR-A, and CNP is mainly combined with NPR-B to exert its biology. The results show that the natriuretic peptide and its receptors are widely distributed in the kidney, but the pathophysiological role of NPs-NPR-cGMP system in renal ischemia-reperfusion is not very important. To this end, we observed and discussed the effect of CNP-NPR-B-cGMP signal pathway in renal ischemia-reperfusion injury from the aspects of morphology and molecular biology. Using the model of renal ischemia-reperfusion in rats, serum samples were prepared to determine renal function indices such as creatidine, Cr, blood urine, and so on, and renal tissue morphology was observed by light microscope and electron microscope. The concentrations of CNP and NPR-B mR were observed by RT-PCR and immunohistochemistry. In addition, 24 SD rats were randomly divided into sham operation group (sham), renal ischemia reperfusion group (IR) and renal ischemia-reperfusion instant CNP administration group (IR + CNP) (8 rats in each group). Serum Cr, NPY and SOD in renal tissues were determined. The activity and MDA content were observed, and the morphological changes of renal tissues were observed by light microscope and the expression of Bax and Bc in renal tissues were observed by western blot technique. expression change of l-2 The results of the experiment were as follows: 1. The levels of serum Cr and NPY in renal ischemic reperfusion group were significantly higher than that in sham operation group (n = 8, P <0.01). 01) Time-dependent characteristics were presented and time-dependent characteristics were presented. 2. The renal tissue structure of the sham-operated group was clear, the renal tubular epithelial cells were intact, only mild inflammatory cell infiltration was observed. It was seen that the renal medulla was dark red; the cortex was swollen and pale. Under the microscope, the vacuoles and degeneration of the proximal tubular epithelial cells of the IR group were observed, the cells were flat, the lumen of the tube was expanded, the brush-like margin disappeared, and the epithelial, tubular and inflammatory exudates were removed in the lumen of the tube. The basement membrane was exposed. Even the segmental focal necrosis of the renal tubular cells. There is a different degree of inflammatory cell infiltration and edema in the stroma. The distal tubules and the lumen of the collection tube are visible cell debris or particle casts, tubular basement membrane segment fracture, fracture site visible lymphocytes, monocytes Neutrophil infiltration, renal interstitial diffusion and edema were observed. The ultrastructures under electron microscope of sham group were basically normal, the mitochondria were intact, swelling was not observed, the structure of rough reticulum was complete, the arrangement was orderly, and the microvilli of renal tubular epithelial cells showed off in the IR group under electron microscope. Swelling of granule, disappearance of mitochondrial membrane, dilatation of ER, primary and secondary dissolution There is an increase in the number of enzymes, and an increase in the number of cells can be seen. Even the epithelial cells Disintegration, only visible or broken basal membrane. 3. sham operation group and ischemia-reperfusion group for different time periods (0/ 1/ 2/ 4h) serum C There was no significant difference in NP content (n = 8, P0.05). The expression of NPR-B was highest (n = 8, P 0.05). 5. Both the sham operation group and the renal tissue NPR-B of the ischemia-reperfusion group were positive. Compared with the reperfusion group, the positive brown granules increased significantly, and the staining was significantly increased. The expression of NPR-B mRNA in renal tissues of rats was significantly higher than that in normal control group. The dirty volume is obviously increased and the quality is soft; the section is seen in the medulla of the kidney; the renal medulla is dark red; the cortex is swollen and pale. The near-end tubular epithelial cell vacuoles and particle degeneration under the microscope, the cell is flat, the tube cavity is expanded, the brush-like edge falls off, and the exfoliated epithelium, the tube and the tube cavity are formed in the tube cavity. Inflammatory exudate, bare basement membrane, and even segmental focal necrosis of tubular cells. Renal tubular stroma can have varying degrees of inflammatory cells. Infiltration and edema, visible cell debris or particle casts in the distal tubules and manifold lumen. Tubular basement membrane segment fracture, fracture Site visible lymphocytes, monocytes, and neutralizing Neutrophil infiltration, renal interstitial diffuse edema. No significant changes in glomerular and renal function were found. Renal tubular arrangement of CNP group After 24 hours of ischemia-reperfusion group, the level of serum Cr and NPY was significantly higher than that of sham-operated group (n = 8, P0.001). (n = 8, P0.05). Compared with the sham operation group, the content of MDA increased significantly and the activity of SOD decreased significantly (n = 8, P0.01 and P0.05). Compared with sham operation group and CNP, the expression of Bax was significantly increased (n = 8, P0.05). Significant differences, but C The ratio of Bax/ Bcl-2 decreased (n = 8, P0.05). Results: 1. The structure and function of tissue were obviously damaged during renal ischemia-reperfusion. especially at the junctional region and medulla of the skin. The expression of NPR-B was obviously up-regulated. To improve the structure and function of kidney tissue damaged by ischemia-reperfusion injury, and present an anti-injury effect.
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2011
【分類號(hào)】：R363
【參考文獻(xiàn)】
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