气体信号分子硫化氢与肾脏疾病研究进展

一直以来,硫化氢（hydrogen sulfide,H2S）被看作是具有臭鸡蛋气味的有毒气体,但是在包括人在内的哺乳动物体内都可以内源性的生成H2S气体。目前,H2S在心血管、神经、消化、呼吸、内分泌、血液以及免疫系统中的生物学效应已得到逐步认识     

气体信号分子硫化氢的研究进展

背景 硫化氢(hydrogen sulfide,H2S)长期以来一直被视为是一种有毒废气,近年来的研究表明,H2S作为最新发现的内源性气体信号分子,具有重要的生物学活性,广泛参与机体的多种生理、病理过程. 目的 探讨H2S的生理病理以及与疾病的关系,并就其研究进展作一综述. 内容 H2S不仅对全身多系统的缺血性等疾病有治疗作用,对神经性及炎症性疼痛的双向性调节作用更是关系密切,其机制可能与其是内源性血管平滑肌的ATP敏感性钾通道(ATP-sensitive potassiumchannel,KATP)开放剂及具有抗氧化作用相关. 趋向 H2S这些新用途对探寻临床相关疾病的有效治疗方法具有重要意义,未来研究重点应在H2S对于疼痛作用的确切机制上.     

硫化氢——具有临床应用潜力的气体信号分子

背景 硫化氢(hydrogen sulphide,H2S)是人们发现的第3个内源性气体信号转导分子,参与了许多疾病的发生发展过程,并且发现H2S相关药物对于某些疾病治疗取得了较为满意的结果.目的 总结H2S在中枢神经系统、心血管系统等的作用以及相关机制.内容 从中枢神经系统、心血管系统、呼吸系统、消化系统、炎症反应以及...     

硫化氢在心血管疾病中的作用

内源性硫化氢是第3个被发现的气体信使分子.在心血管系统,硫化氢主要由胱硫醚-γ-裂解酶催化合成,参与心血管生理功能的调控和病理生理过程,具有舒张血管、降低血压、抑制血管平滑肌细胞增生、抗氧化等多种生物学效应,与高血压、高血脂、动脉粥样硬化、冠心病等多种心血管疾病相关,本文将对内源性硫化氢的生化、生理特性,在心血管疾病中的病理生理作用等有关问题进行概述.     

气体信号分子硫化氢与心肌保护

硫化氢可以在哺乳动物循环系统内源性产生.硫化氢能减轻心肌缺血/再灌注损伤,这一保护作用的机制包括:清除自由基、抑制炎症反应、保护线粒体功能、有关信号通路激活、ATP敏感性钾通道开放.     

硫化氢在中枢神经系统的生理及保护作用

背景 长期以来硫化氢(hydrogen sulfide,H2S)都被认为是造成环境污染的有毒气体.后来研究发现,哺乳动物体内的H2S是一种具有生理调节作用的内源性气体介质,具有多种生物学功能.H2S与一氧化氮(nitric oxide,NO)、一氧化碳(carbon monoxide,CO)共同组成了气体信号分子家系.过去十年里,有关H2S在生理和病理过程中的作用,尤其是在中枢神经系统和心血管系统中的作用,进行了大量研究.目的 阐释当前H2S在中枢神经系统的生理及保护作用研究进展.内容 简要描述H2S在中枢神经系统的合成、调节以及生理功能 ;重点介绍H2S中枢神经系统保护作用的可能机制.趋向 通过阐述H2S在中枢神经系统的生理及保护作用机制,为H2S用于神经系统相关疾病的治疗提供新的思路.     

新型气体信号分子H2 S与骨质疏松的研究概况

骨质疏松症已是当代世界关注的的健康问题之一,了解骨代谢的精确机制及影响因素成为主要的研究焦点。研究发现,H_2S作为一种新型内源性气体信号分子已被广泛认可,并发现可以作为骨平衡稳态的重要调节剂。H_2S可以通过抑制氧化应激、调节骨间质细胞Ca~(2+)通道、促进特异性基质金属蛋白酶(MMP)活性,调节骨代谢平衡,从而预防和治疗绝经后和长期使用糖皮质激素等导致的骨质疏松症。对内源性H_2S作用机制研究的同时,为帮助H_2S的临床研究,H_2S的外源性供体的试验的研究也逐步开展。本文对现有研究进行了总结,旨在为H_2S进一步的研究提供帮助。     

新型气体信号分子——硫化氢心肌保护作用的研究进展

研究发现,硫化氢是继一氧化氮和一氧化碳后的第3个内源性气体信号分子.现就近年来关于硫化氢可影响多种细胞信号转导通路,具有开放ATP敏感性钾通道(ATP-sensitive potassium channels,KATP)通道、抗氧化、抗炎的保护性效应并可作用于线粒体电子传递链在保护缺血/再灌注心肌方面的研究进展作一综述.     

气体信号分子硫化氢对大鼠重症急性胰腺炎肺损伤的影响

目的 探讨气体信号分子硫化氢(H2S)对大鼠重症急性胰腺炎(SAP)肺损伤的影响.方法 60只Wistar大鼠随机分为4组(每组15只):假手术(sham)组、SAP组、硫氢化钠干预(NaHS)组和炔丙基甘氨酸干预(PAG)组.NaHS组和PAG组分别于造模后1h经腹腔注射NaHS和PAG.各组于造模24 h后测定肺组织胱硫醚γ-裂解酶活性及mRNA表达、髓过氧化物酶、磷脂酶A2、核因子κB活性、湿/干重比及细胞间黏附分子-1(ICAM-1)、P物质、丙二醛、肿瘤坏死因子、白细胞介素-1水平.对胰腺及肺组织进行病理学检查,检测血H2S、肿瘤坏死因子及白细胞介素-1含量.结果 与SAP组相比,NaHS组各项指标均明显升高(P＜0.05),而PAG组各项指标均显著降低(P＜0.05).结论 SAP时,内源性H2S水平明显增加,对SAP并发肺损伤起到了重要的促进作用.以H2S为靶点,抑制系统和组织H2S生成对SAP继发肺损伤可起到一定的保护作用,其机制可能与抑制过度炎症反应、减轻氧化应激损伤和改善微循环障碍等有关.     

气体信号分子H2S与中枢神经系统的关系研究进展

细胞的信号分子有3种类型:亲脂性信号分子、亲水性信号分子、气体性信号分子。近年来气体信号分子在细胞信号转导中的作用备受关注。Abe等[1]1996年首次通过实验证明内源性H2S可能作为一种神经活性物质而存在。Wang[2]总结近年相继发现的两种内源性气体信号分子———一氧化氮(     

Hydrogen Sulfide Inhibits Plasma Renin Activity

The development of renovascular hypertension depends on the release of renin from the juxtaglomerular (JG) cells, a process regulated by intracellular cAMP. Hydrogen sulfide (H₂S) downregulates cAMP production in some cell types by inhibiting adenylyl cyclase, suggesting the possibility that it may modulate renin release. Here, we investigated the effect of H₂S on plasma renin activity and BP in rat models of renovascular hypertension. In the two-kidney-one-clip (2K1C) model of renovascular hypertension, the H₂S donor NaHS prevented and treated hypertension. Compared with vehicle, NaHS significantly attenuated the elevation in plasma renin activity and angiotensin II levels but did not affect plasma angiotensin-converting enzyme activity. Furthermore, NaHS inhibited the upregulation of renin mRNA and protein levels in the clipped kidneys of 2K1C rats. In primary cultures of renin-rich kidney cells, NaHS markedly suppressed forskolin-stimulated renin activity in the medium and the intracellular increase in cAMP. In contrast, NaHS did not affect BP or plasma renin activity in normal or one-kidney-one-clip (1K1C) rats, both of which had normal plasma renin activity. In conclusion, these results demonstrate that H₂S may inhibit renin activity by decreasing the synthesis and release of renin, suggesting its potential therapeutic value for renovascular hypertension.Renovascular hypertension is a common secondary hypertension and the most prevalent form of curable hypertension.¹ Although presently used antihypertensive agents have been shown to reduce the incidence of cardiovascular events, achievement of blood pressure (BP) control continues to be a worldwide public health problem. Hence, newer antihypertensive agents are needed to expand therapeutic options, increase treatment efficacy, decrease side effects, and enhance patient adherence.Hydrogen sulfide (H₂S) is considered as a novel gasomodulator besides nitric oxide and carbon monoxide.^2,3 It is produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS),⁴ and a newly identified enzyme, 3-mercaptopyruvate sulfurtransferase.⁵ The expression of these enzymes has been identified in many human and other mammalian cells, including those from liver, kidney, brain, and blood lymphocytes.⁶ We and other groups previously report H₂S plays important roles in numerous physiologic and pathologic processes such as cardioprotection, neurotransmission, inflammatory processes, etc.^6–9 In vascular vessels, it was reported that H₂S is a physiologic vasodilator.^10–12 Recently, it was reported that inhibition of endogenous H₂S production by knockout of cystathionine γ-lyase (CSE^−/−) may cause hypertension in mice.¹³BP is controlled by the renin-angiotensin system (RAS). Excessive activity of RAS can result in hypertension and disorders of fluid and electrolyte homeostasis. Pharmacologic blockade of RAS has been available for almost 25 years. There is extensive documentation of its effectiveness in the treatment of hypertension. The renin-angiotensinogen reaction is the first and rate-limiting step in the production of angiotensin II (Ang II) and thus could be a therapeutic target for the treatment of hypertension. Renin is predominantly regulated by intracellular cAMP in juxtaglomerular (JG) cells. We previously reported that H₂S may downregulate cAMP production via inhibition of adenylyl cyclase (AC) activity in the heart and vascular smooth muscle cells.^12,14 We therefore hypothesized that H₂S may also regulate BP by inhibition of renin release.Among the experimental models of hypertension, the renovascular model has brought considerable insights to studies of the pathophysiology of hypertension.^15–17 The two-kidney-one-clip (2K1C) model is an ideal animal model of renovascular hypertension. The reduction in pressure caused by stenosis of the renal artery decreases the GFR, which in turn causes the quantity of filtered solutes to fall.¹⁸ Macula densa cells present in the JG apparatus are able to detect these changes and induce the nearby granular cells to release renin, which in turn induces hypertension. In contrast, the development and maintenance of hypertension in the one-kidney-one-clip (1K1C) model is mainly related to sympathetic drive,^15,19 local angiotensin converting enzyme (ACE) activity (particularly in organs regulating hypertension such as the aorta and heart),²⁰ and Na⁺/H₂O retention.^21,22 The transient elevation of renin (within the first day after clipping) is only responsible for the onset of development of hypertension in the 1K1C model.²³ The maintenance of hypertension has been considered to be independent of the circulating RAS with normal or low plasma renin activity (PRA).²⁴The study presented here was designed to examine the effect of H₂S on RAS and its role in renovascular hypertension with 2K1C and 1K1C rat models. The underlying mechanism was investigated in in vivo and in vitro studies.     

外源性硫化氢对急性坏死性胰腺炎的影响

目的探讨硫化氢（H2S）对急性坏死性胰腺炎（ANP）的影响。方法 43只SD雄性大鼠按数字表法行完全随机分组：假手术组（n=4）;ANP组（n=21）,该组再均分为3、6及12 h 3个亚组（n=7）;NaCl＋ANP组（n=4）;NaHS＋ANP组（n=7）;以及炔丙基甘氨酸（PAG）＋ANP组（n=7）。通过胰胆管逆行注射5%牛磺胆酸钠制作ANP模型;NaCl＋ANP组、NaHS＋ANP组及PAG＋ANP组大鼠均在模型制作术前1 h分别给予生理盐水、NaHS及PAG进行预处理。检测各组大鼠血清淀粉酶（AMY）、谷草转氨酶（AST）、谷丙转氨酶（ALT）、血尿素氮（BUN）及血肌酐（Cr）水平,并观察胰腺组织的病理组织学改变。结果 ANP组大鼠制模术后血清AMY、AST、ALT、BUN及Cr水平进行性升高。NaHS＋ANP组大鼠血清AMY、AST、ALT、BUN及Cr水平高于NaCl＋ANP组（P〈0.05）,胰腺组织的病理损伤也较NaCl＋ANP组严重。PAG＋ANP组大鼠血清AMY、AST、ALT、BUN及Cr水平则低于NaCl＋ANP组（P〈0.05）,胰腺组织的病理损伤也较NaCl＋ANP组轻。结论 ANP肝、肾及胰腺功能受损可能与H2S浓度升高有关,预防性给予H2S阻断剂PAG可改善肝、肾及胰腺功能,具有器官保护作用。     

硫化氢在重症急性胰腺炎患者血浆中的表达及意义

目的:探讨硫化氢(H2S)在重症急性胰腺炎患者血浆中的表达及意义。方法:重症急性胰腺炎(A组)患者40例,同期健康体检者40例为正常对照组(B组)。敏感硫电极法测定血浆H2S浓度,化学法测定血浆NO含量,采用ELISA检测血浆中TNF-α、IL-6、高敏C反应蛋白(hsCRP)表达。结果:A组TNF-α、IL-6、hsCRP、NO及H2S均显著高于B组(P<0.01),H2S与TNF-α、IL-6、hsCRP、NO呈正相关(r=0.612、0.743、0.629、0.649,P<0.01)。结论:内源性H2S是一种炎症介质,在重症急性胰腺炎中起促进炎症反应效应。     

尿足细胞及其相关分子在肾小球疾病中的表达

目的：探讨尿液检测局灶节段性肾小球硬化足细胞损伤与其他足细胞病之间的特点和差异。方法：入选原发性局灶节段性肾小球硬化（KSGS）患者54例,膜性肾病（MN）23例及微小病变（MCD）12例,正常对照20例。免疫荧光法计数尿足细胞,荧光实时定量PCR法定量尿沉渣足细胞相关分子nephrin、podocin、synaptopodin mRNA的表达水平,Western印迹法检测尿液WilmsTumor1（WT1）蛋白水平,免疫荧光法检测肾脏组织podocalyxin的表达及分布。结果：（1）FSGS组、MN组、MCD组和对照组尿足细胞阳性率分别是63％、34．8％、33．3％和0,FSGS组与其余各组相比差异均有统计学意义（P〈0．05）。FSGS组足细胞脱落数目显著高于MCD组、MN组和对照组（P〈0．05）,伴足细胞尿FSGS患者与不伴足细胞尿FS—GS患者相比,24h尿蛋白和血清白蛋白（Alb）差异均有统计学意义（P〈0．05）。（2）FSGS组尿沉渣足细胞nephrin mRNA表达水平显著高于MCD和MN组（P〈0．05）;FSGS组尿沉渣足细胞podocinmRNA表达显著高于MCD组（P〈0．05）,与MN组相比有升高趋势但差异无统计学意义;尿沉渣足细胞synaptopodin mRNA表达各组间差异无统计学意义。尿沉渣足细胞nephrin、podocin．synaptopodin mRNA的表达与24h蛋白尿无相关性。（3）FSGS组尿WT1蛋白量显著高于MCD和MN组。部分足细胞阴性患者尿液检测到WT1分子。（4）FSC-S患者肾组织podocalyxin较对照组、MCD和MN有明显的节段缺失。结论：局灶节段性肾小球硬化病患者足细胞损伤严重,尿足细胞与FSGS疾病活动相关。尿沉渣足细胞nephrin mRNA表达可以把FSGS与MCD和MN区分开来,尿WT1蛋白可能是足细胞早期损伤指标。     

硫化氢对脓毒症大鼠动脉压力反射的影响

目的 探讨硫化氢(H2S)对脓毒症大鼠动脉压力反射(ABR)的作用及机理.方法 盲肠结扎穿刺(CLP)法制作脓毒症大鼠模型,选取47只雄性Spargue-Dawley大鼠随机分为9组:①假手术(SO)+0.9%NaCl(NS)静脉注射组;②SO+硫氢化钠(NaHS)静脉注射组;③CLP+Naris静脉注射组;④SO+人工脑脊液(aCSF)双侧孤束核(NTS)注射组;⑤SO+NariS双侧NTS注射组;⑥SO+安慰剂(DMSO)+Naris组;⑦SO+格列苯脲(Gli)+Naris组;⑧CLP+安慰剂(DMSO)组;⑨CLP+GIi组.分别在给药前、给药后5 min和30 Min 3个时间点对各组大鼠的ABR功能进行测定.结果 ①同一组内不同时相问ABR值的变化结果:与给药前比较,SO+NaHS静脉注射组、CLP+NariS静脉注射组、SO+NaHS双侧NTS注射组及SO+安慰剂+NaHS组给药后5 min和30 minABR值均明显降低(P<0.05,P<0.01),而CLP+Gli组明显升高(P<0.05).②相同时相不同组间ABR值的变化结果:给药前,CLP+NaHS静脉注射组明显低于SO+NS静脉注射组或SO+NaHS静脉注射组(P<0.05);给药后5 min和30 min,CLP+NaHs静脉注射组明显低于SO+NS静脉注射组或SO+NaHS静脉注射组(P<0.05),SO+NaHS静脉注射组明显低于SO+NS静脉注射组(P<0.05);SO+NaHS双侧NTS注射组明显低于SO+aCSF双侧NTS注射组(P<0.01);SO+Gli+NaHS组明显高于SO+安慰剂+NaHs组(P<0.05);CLP+Gli组明显高于CLP+安慰剂组(P<0.05).结论 脓毒症H2S生成增加对ABR功能有降低作用,该作用可能与ATP敏感性钾通道开放有关;脓毒症状态下H2S不仅通过外周静脉系统发挥作用,而且可能通过中枢NTS影响ABR功能.     

硫化氢复合浅低温可选择性激活突触内NMDARs及其下游CREB信号通路

目的：观察硫化氢复合浅低温对大鼠全脑缺血再灌注后海马N-甲基-D-天冬氨酸受体（NMDARs）的亚单位NR2A、NR2B及其环磷酸腺苷反应元件结合蛋白（CREB）信号通路的影响,旨在探讨其是否存在脑复苏作用及发挥作用的潜在机制。方法：雄性SD大鼠随机分为以下五组（n=20）：假手术组（Ⅰ）、模型维（Ⅱ）、浅低温组（Ⅲ）、NaHS组（Ⅳ）,浅低温＋NaHS组（Ⅴ）。采用Pulsinelli-Brierley四血管阻塞法建立大鼠全脑缺血再灌注损伤模型,缺血15min,再灌注即刻Ⅳ组和Ⅴ组腹腔注射14μmol／kgNaHS。Ⅲ组和Ⅴ组行体表降温至肛温32～33℃。6h后断头取海马,分别采用分光光度计法测H2S的含量．westernblot法测NR2A、NR2B以及p-CREB的表达．RT-PCR法测BDNFmRNA的水平．每组分别职4只于再灌注72h取脑行HE染色观察CA1区锥体细胞病理改变。结果：①与Ⅰ组相比,各组海马组织H2S含量均升高（P〈0．05）;与Ⅱ组相比,Ⅲ组含量略升高（P〉0．05）,Ⅳ和Ⅴ组显著升高（P〈0．05）;②与Ⅰ组相比．各组NR2A、NR2B的灰度值均增高（P〈0．05）．且Ⅱ和Ⅲ组NR2A／NR2B〈1,Ⅳ和Ⅴ组NR2A／NR2B〉1;③与Ⅱ组相比。Ⅲ-Ⅴ组p-CREB及BDNFmRNA的表达均显著升高（P〈0．05）;④与Ⅱ组相比．Ⅲ-Ⅴ组CA1区锥体细胞损伤程度均明显减轻．尤以Ⅴ组效果昂佳。结论：硫化氢复合浅低温可通过选择性作用于突触内的NMDARs．进而激活其下游促存活CREB信号通路．从而发挥脑复苏的作用。     

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

Soluble fms-like tyrosine kinase 1 (sFlt1), a circulating antiangiogenic protein, is elevated in kidney diseases and contributes to the development of preeclampsia. Hydrogen sulfide is a vasorelaxant and proangiogenic gas with therapeutic potential in several diseases. Therefore, we evaluated the potential therapeutic effect and mechanisms of action of hydrogen sulfide in an animal model of sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis created by adenovirus-mediated overexpression of sFlt1 in Sprague-Dawley rats. We injected sFlt1-overexpressing animals intraperitoneally with the hydrogen sulfide–donor sodium hydrosulfide (NaHS) (50 µmol/kg, twice daily) or vehicle (n=7 per group). Treatment with NaHS for 8 days significantly reduced sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis. Measurement of plasma protein concentrations with ELISA revealed a reduction of free plasma sFlt1 and an increase of free plasma vascular endothelial growth factor (VEGF) after treatment with NaHS. Renal VEGF-A mRNA expression increased significantly with NaHS treatment. In vitro, NaHS was proangiogenic in an endothelial tube assay and attenuated the antiangiogenic effects of sFlt1. Stimulation of podocytes with NaHS resulted in both short-term VEGF release (120 minutes) and upregulation of VEGF-A mRNA levels (24 hours). Furthermore, pretreatment of mesenteric vessels with a VEGF receptor 2–neutralizing antibody significantly attenuated NaHS-induced vasodilation. These results suggest that hydrogen sulfide ameliorates sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis in rats by increasing VEGF expression. Further studies are warranted to evaluate the role of hydrogen sulfide as a novel therapeutic agent for vascular disorders such as preeclampsia.Elevated soluble fms-like tyrosine kinase 1 (sFlt1, also referred to as soluble vascular endothelial growth factor receptor 1) levels are associated with several diseases, including preeclampsia, vasculitis, and CKD.^1–3 In preeclampsia, a consistent line of evidence has shown that increased sFlt1 is one of the major contributors to the development of hypertension and proteinuria.^4–7 sFlt1 is a splice variant of the vascular endothelial growth factor (VEGF) receptor lacking the transmembrane and cytoplasmic domains and acts as a powerful antagonist of VEGF, thereby inhibiting VEGF signaling in the vasculature.^8–10 Increased levels of circulating sFlt1 lead to functional VEGF deficiency, causing endothelial dysfunction, decreased angiogenesis, impaired capillary repair, and consequently hypertension and proteinuria.^5,11 Indeed, VEGF inhibitors used as part of cancer chemotherapy are associated with significant hypertension and proteinuria.^12–14 Moreover, genetic models of glomerular VEGF deficiency are also associated with proteinuria and glomerular endothelial damage.^13,15 Thus far, no targeted inventions to reduce circulating sFlt1 are available in the clinic. Although recombinant VEGF or placental growth factor have proven to be effective in experimental models, no clinical trials have yet been conducted .^16–19 sFlt1 removal using dextran sulfate apheresis has recently shown to be a possible new strategy in patients with very severe preterm preeclampsia.²⁰Hydrogen sulfide (H₂S) belongs to a family of gasotransmitters, along with nitric oxide and carbon monoxide. The endogenously produced gas is important in physiologic processes, such as regulating arterial diameter, blood flow, and leukocyte adhesion.²¹ H₂S has been shown to enhance vasorelaxation through an endothelial cell–independent mechanism by acting on ATP-sensitive potassium (K_ATP) channels.^22,23 However, K_ATP channel blockers do not completely abolish H₂S-induced relaxation, and H₂S stimulates vasorelaxation in an endothelial cell–dependent manner at lower doses.^24–27 This suggests that H₂S likely stimulates vasorelaxation through additional pathways that have not yet been elucidated.In several animal models, endogenous activity of H₂S-producing enzymes and exogenous H₂S donors or precursors protect against ischemia and reperfusion injury and exhibit anti-inflammatory activity.^28–31 The proangiogenic effect of H₂S was first described by Cai et al., who showed that an exogenously administrated H₂S donor (sodium hydrosulfide [NaHS]) promoted proliferation, migration, and tube-like structure formation in endothelial cells in vitro.³² In vivo, it was demonstrated that H₂S is a proangiogenic factor in a model of hind limb ischemia.³³ These effects were associated with an increase in VEGF expression and activation of vascular endothelial growth factor receptor (VEGFR)2 signaling in vascular endothelial cells, suggesting that the effects of H₂S may be mediated by VEGF and its receptor VEGFR2.³³ Bir et al. recently showed that H₂S-stimulated ischemic vascular growth is dependent on augmented expression and activity of VEGF.³⁴We therefore hypothesized that by upregulating VEGF, H₂S may directly antagonize the detrimental effects of sFlt1 on the endothelium, consequently attenuating the development of hypertension and proteinuria. In this study, we demonstrate a protective effect of exogenous H₂S administration in a rat model with overt hypertension and proteinuria induced by sFlt1 overexpression.