ATP-P2X4信号轴介导NLRP3炎性体的活化：一种糖尿病肾病肾间质炎症发生的新途径
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摘要
1.前言
糖尿病肾病(Diabetic Nephropathy,DN)是导致终末期肾脏疾病的主要病因。肾间质炎症反应是糖尿病肾病的重要病理生理基础。IL-1家族细胞因子是糖尿病肾病炎症反应的主要调节器,与糖尿病各种慢性并发症具有直接关系。IL-1β和IL-18等IL-1家族细胞因子前体分子必须依赖Caspase-1的剪切作用才能发挥生物学作用。研究发现NLRP3炎性体作为胞内危险相关分子模式(DAMPs)的感受器,通过激活Caspase-1调控IL-1p、IL-18等细胞因子的成熟和分泌,引发糖尿病、肥胖症、痛风等代谢相关性疾病中的炎症。有研究发现NLRP3基因敲除后肾脏UUO和缺血再灌注小鼠模型肾小管损伤和肾间质炎症反应显著减轻。最新研究发现STZ糖尿病大鼠肾脏组织中NLRP3炎性体被激活。阻断其活化能明显减轻肾组织炎症反应,改善肾脏功能。这些证据提示NLRP3炎性体在调控肾脏无菌性炎症过程中发挥关键作用。目前糖尿病肾病时NLRP3炎性体的活化机制尚不清楚。
P2X受体活化介导ATP、二聚糖、淀粉样蛋白等内源性DAMPs激活NLRP3炎性体,调控过敏症、急性胰腺炎和癌症等疾病中的无菌性炎症反应,影响患者的疗效和预后。P2X受体是P2受体家族中的一类配体门控离子通道受体,共有七个成员(P2X1-7)。除了P2X3以外的6种P2X受体亚型在肾脏中均有表达。肾小管上皮细胞上主要表达P2X4和P2X6。生理状态下,P2X受体的活化能促进肾脏钠水排泄和调控肾脏的血流量。ATP是P2X受体的激动剂。糖尿病时,高糖依赖细胞外ATP(eATP)激活肾小球系膜细胞上P2X7受体,上调TGF-β和细胞外基质的表达。高糖还可以依赖细胞外ATP引起视网膜细胞caspase-1的活化和IL-1β的分泌。本研究旨在探明ATP-P2X4信号轴在糖尿病肾病肾间质炎症反应中的作用,为解析糖尿病肾病肾脏炎症的发病机制以及寻找防治糖尿病肾病的新措施提供理论依据。
2.方法：
2.1临床病例
选取2011年1月至2012年6月重庆大坪医院肾内科收治的2型糖尿病肾病患者45例,纳入标准为：40-70岁；有2型糖尿病病史；24h尿蛋白>150mg；经肾活检病理诊断为糖尿病肾病；不包括发烧或有明显感染病灶,以及高尿酸患者；所有病例使用胰岛素控制血糖,利用血管紧张素拮抗剂和CCB类降压药控制血压,以及他汀类控制血脂,在行肾活检3月内未服用任何中药或者格列苯脲等降糖药。对照组为11例肾错构瘤患者,其肾组织标本均取自切除肾脏的远离肿瘤部分经病理检查为正常肾组织。
常规生化方法测定血清总胆固醇、低密度胆固醇、SCr、24h尿蛋白定量,并根据公式计算eGFR值。利用免疫荧光和免疫组化检测患者肾小管P2X4、NLRP3、IL-1β、 IL-18的表达情况。并分析肾小管上皮细胞P2X4、NLRP3和尿IL-1β、IL-18水平之间的相关性。
2.2细胞培养
HK-2细胞,作为一种肾小管上皮细胞株,培养于含胎牛血清10%的低糖DMEM培养基。HK-2细胞在无血清DMEM中静止12h,1)分别以35mM D-glucose或5mM D-glucose+30mM甘露醇作用于HK-2细胞0、12、24、48、72小时；2)分别培养于正常糖浓度,高糖浓度,高甘露醇浓度,作用48小时。分别利用apyrase (eATP水解酶),suramin(P2受体拮抗剂),TNP-ATP(P2X受体拮抗剂),或者5-BDBD(P2X4受体拮抗剂)和35mM D-glucose共同作用于HK-2细胞48h。
利用ATP荧光素检测试剂盒检测细胞上清液中ATP的表达水平。利用PBFI-AM检测细胞内钾离子浓度,利用Fluo-3/AM检测细胞内钙离子浓度。利用western blot检测细胞内NLRP3、细胞上清液中成熟的caspase-1和IL-1β的表达,利用ELISA检测细胞上清液中IL-1β和IL-18的水平。
2.3细胞转染
分别以脂质体LipofectamineTM2000加对照Green-Fluorescein Conjugate对照siRNA、无荧光标记对照siRNA、或者P2X4siRNA,转染肾小管上皮细胞24h后,进行高糖刺激48h。
利用PBFI-AM检测细胞内钾离子浓度,利用Fluo-3/AM检测细胞内钙离子浓度。利用western blot检测细胞内NLRP3、细胞上清液中成熟的caspase-1和IL-1β的表达,利用ELISA检测细胞上清液中IL-1β和IL-18的水平。
3.结果：
3.1肾小管上皮细胞P2X4表达与DN肾间质炎症相关
2型糖尿病肾病患者肾小管上皮细胞P2X4和NLRP3表达水平明显升高。P2X4和NLRP3的免疫组化表达评分分别和尿IL-1β、IL-18水平均呈正相关关系。免疫荧光结果显示P2X4的表达分别和NLRP3、IL-1β、IL-18蛋白呈共定位现象。
3.2高糖依赖细胞外ATP激活NLRP3炎性体
高糖刺激下HK-2细胞内NLRP3的表达、细胞上清液中成熟的caspase-1和IL-1p的表达、以及细胞分泌IL-1β、几-18和ATP的水平呈明显剂量和时间依赖性升高。Apyrase消耗掉细胞外ATP,能完全阻断高糖上调NLRP3、成熟的caspase-1、IL-1β和总IL-1p、IL-18的表达。
3.3高糖引起HK-2细胞的ATP-P2X4信号轴活化
高糖刺激导致HK-2细胞内钾离子浓度浓度明显下降,钙离子浓度明显上升。Apyrase能够明显抑制高糖诱导的HK-2细胞内钾离子浓度的降低和钙离子浓度的升高。Suramin、TNP-ATP、5-BDBD均能显著抑制高糖引起细胞内钾离子浓度的降低。TNP-ATP、5-BDBD均能抑制高糖引起细胞内钙离子浓度的升高。
3.4P2X4受体介导高糖激活NLRP3炎性体
Suramin、TNP-ATP以及5-BDBD均能够明显抑制高糖上调NLRP3、成熟的caspase-1、IL-1β和总IL-1β、IL-18的表达。P2X4siRNA转染能够明显抑制的高糖引起的细胞内低钾高钙,以及NLRP3、成熟的caspase-1、IL-1β和总IL-1p、IL-18表达的升高。
4.结论：
ATP-P2X4轴通过介导高糖依赖细胞外ATP激活NLRP3炎性体,调控IL-1家族细胞因子的成熟和分泌,在引发糖尿病肾病肾间质炎症反应中发挥着关键作用。
1. Background
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease Tubulointerstitial inflammation is crucial in promoting the development and progression of DN. Interleukin-1(IL-1) family cytokines have an initiating role in early stages of inflammation in DN. They have direct relationships with many chronic complications of diabetes. Pro-IL-1β and pro-IL-18, the precursor molecules of IL-1family cytokines, rely on caspase-1shearing action to exert their biological effects. The NOD-like receptor3(NLRP3) inflammasome, the intracellular receptor of dangerous related molecular pattern (DAMP), can activate caspase-1, regulate IL-1β and IL-18maturation and secretion, and trigger the inflammation of metabolic diseases such as diabetes, obesity, and gout. NLRP3knock-out mice are protected from renal tubule damage and renal interstitial inflammation in kidney unilateral ureteral occlusion (UUO) and ischemia-reperfusion models. The NLRP3inflammasome is activated in kidney tissue of streptozotocin-induced diabetic rats, and both quercetin and allopurinol can significantly reduce renal tissue inflammation and improve renal function by blocking NLRP3inflammasome activation. These data show that the NLRP3inflammasome plays a key role in the process of kidney sterile inflammation. However, the mechanism of NLRP3inflammasome activation in DN is still not clear.
Activated purinergic P2X receptors mediate endogenous DAMPs such as adenosine triphosphate (ATP), biglycan, and amyloid protein, activate the NLRP3inflammasome, and regulate aseptic inflammation in hypersensitivity, acute pancreatitis and cancer. P2X receptors are ligand-gated ion channel receptors in the P2family. There are seven subtypes (P2X1-7), which are expressed in the kidney with the exception of P2X3. Renal tubule epithelial cells mainly express P2X4and P2X6. ATP is a wide range P2X receptor agonist. Increased extracellular ATP (eATP) induced by hyperglycemia, can activate P2X7receptor of glomerular mesangial cell, and up-regulate TGF-β and extracellular matrix expression in diabetes. Hyperglycemia can also rely on eATP, and cause retinal cell caspase-1activation and IL-1β secretion. The role of P2X4in diabetic nephropathy is still undefined. The purpose of this study is to investigate the role of ATP-P2X4signaling in NLRP3inflammasome activation and renal interstitial inflammation of DN and provide theoretical foundation for analyzing the pathogenesis of renal inflammation and finding new treatments for DN.
2. Methods
2.1Patients
A total of45patients with type2diabetic nephropathy were recruited for this study from the Department of Nephrology in Daping Hospital from January1,2011to June1,2012. The enrollment criteria were as follows:patients were40-70years old with a history of type2diabetes;24h urine protein was above150mg; renal biopsy pathology led to a diagnosis of diabetic nephropathy; and no fever with obvious infection lesions or high uric acid. All patients used insulin to control blood glucose, angiotensin antagonist and CCB to control blood pressure, and statins to control lipids. Patients abstained from traditional Chinese medicine or sulfonylureas for three months after renal biopsy. Normal kidney tissues from nephrectomies of renal hamartoma were collected to be used in the control group.
Serum total cholesterol, LDL cholesterol, SCr,24h urinary protein excretion was measured by biochemical analysis. P2X4, NLRP3, IL-1β and IL-18expression in renal tubule was detected by immunofluorescence and immunohistochemistry. The relationship of P2X4, NLRP3and urinary IL-1β and IL-18were analysed.
2.2Cell culture
HK-2cells were cultured in Dulbecco's modified Eagle's medium with low glucose. The cells were seeded at1.5x106cells/10cm diameter dish for2-3days at37℃in a humidified atmosphere containing5%CO2. HK-2cells were grown in media with normal glucose concentration, or high glucose concentration, or high mannitol concentrations for48h. HK-2cells were incubated in media with high glucose (35mM,48h) with and without apyrase, P2receptor antagonist suramin, P2X receptor antagonist TNP-ATP and P2X4selective antagonist5-BDBD.
ATP levels were determined using an ATP luciferase-based bioluminescence assay kit in a luminometer. Intracellular K+concentration was measured by PBFI-AM. Cytosolic free Ca2+was indicated by Fluo-3/AM. NLRP3protein expression, cleavage of caspase-1and IL-1β were analyzed by Western Blot. Release of IL-1β and IL-18were detected by ELISA.
2.3P2X4siRNA transfection
Transfection control cells were transfected with siRNA for unrelated genes or control siRNA, while experimental cells were transfected with siRNA directed against P2X4, with all transfections utilizing Lipofectamine2000according to the manufacturer's instructions. Cells incubated with Lipofectamine2000were also used as a negative control. P2X4knockdown was confirmed by Western blot and quantitative reverse transcription-PCR (qRT-PCR).
3. Results
3.1P2X4expression related with renal interstitial inflammation in DN
P2X4and NLRP3expression was upregulated in tubular epithelial cells in patients with type2DN. P2X4immunostaining score, as well as NLRP3immunostaining score, was positively correlated with urine IL-1β and IL-18levels. P2X4expression was co-localized with NLRP3, IL-1β, and IL-18expression in the DN group.
3.2High glucose-induced NLRP3inflammasome activation is extracellular ATP-dependent
After stimulation of high glucose, NLRP3expression, cleavage of caspase-1and IL-1β, and release of ATP, IL-1β and IL-18were enhanced in a dose and time dependent way. Apyrase significantly inhibited NLRP3expression, cleavage of caspase-1and IL-1β, and release of IL-1β and IL-18caused by high glucose.
3.3High glucose caused ATP-P2X4signaling activation
High glucose cause intracellular calcium concentration increase, and potassium ion concentration reduce. Apyrase significantly inhibited potassium concentration reduction and calcium concentration increase under high glucose condition. Suramin, TNP-ATP,5-BDBD can significantly inhibit potassium concentration reducing caused by high glucose. Moreover, TNP-ATP,5-BDBD can restrain intracellular calcium concentration increasing cause by high glucose as well.
3.4P2X4receptor mediated NLRP3inflammasome activation caused by high glucose
Suramin, TNP-ATP and5-BDBD all obviously inhibited NLRP3expression, cleavage of caspase-land IL-1β, and release of IL-1β and IL-18with high glucose stimulus. P2X4gene silencing inhibited intracellular potassium efflux and extracellular calcium influx induced by high glucose. The increases in NLRP3expression, cleavage of caspase-land IL-1β, and secretion of IL-1β and IL-18were similarly blunted.
4. Conclusion
ATP-P2X4signaling mediates high glucose-induced activation of the NLRP3inflammasome, regulates IL-1family cytokine secretion, and plays a privotal role in the development of tubulointerstitial inflammation in diabetic nephropathy.
糖尿病肾病(Diabetic Nephropathy,DN)是导致终末期肾脏疾病的主要病因。肾间质炎症反应是糖尿病肾病的重要病理生理基础。IL-1家族细胞因子是糖尿病肾病炎症反应的主要调节器,与糖尿病各种慢性并发症具有直接关系。IL-1β和IL-18等IL-1家族细胞因子前体分子必须依赖Caspase-1的剪切作用才能发挥生物学作用。研究发现NLRP3炎性体作为胞内危险相关分子模式(DAMPs)的感受器,通过激活Caspase-1调控IL-1p、IL-18等细胞因子的成熟和分泌,引发糖尿病、肥胖症、痛风等代谢相关性疾病中的炎症。有研究发现NLRP3基因敲除后肾脏UUO和缺血再灌注小鼠模型肾小管损伤和肾间质炎症反应显著减轻。最新研究发现STZ糖尿病大鼠肾脏组织中NLRP3炎性体被激活。阻断其活化能明显减轻肾组织炎症反应,改善肾脏功能。这些证据提示NLRP3炎性体在调控肾脏无菌性炎症过程中发挥关键作用。目前糖尿病肾病时NLRP3炎性体的活化机制尚不清楚。
P2X受体活化介导ATP、二聚糖、淀粉样蛋白等内源性DAMPs激活NLRP3炎性体,调控过敏症、急性胰腺炎和癌症等疾病中的无菌性炎症反应,影响患者的疗效和预后。P2X受体是P2受体家族中的一类配体门控离子通道受体,共有七个成员(P2X1-7)。除了P2X3以外的6种P2X受体亚型在肾脏中均有表达。肾小管上皮细胞上主要表达P2X4和P2X6。生理状态下,P2X受体的活化能促进肾脏钠水排泄和调控肾脏的血流量。ATP是P2X受体的激动剂。糖尿病时,高糖依赖细胞外ATP(eATP)激活肾小球系膜细胞上P2X7受体,上调TGF-β和细胞外基质的表达。高糖还可以依赖细胞外ATP引起视网膜细胞caspase-1的活化和IL-1β的分泌。本研究旨在探明ATP-P2X4信号轴在糖尿病肾病肾间质炎症反应中的作用,为解析糖尿病肾病肾脏炎症的发病机制以及寻找防治糖尿病肾病的新措施提供理论依据。
2.方法：
2.1临床病例
选取2011年1月至2012年6月重庆大坪医院肾内科收治的2型糖尿病肾病患者45例,纳入标准为：40-70岁；有2型糖尿病病史；24h尿蛋白>150mg；经肾活检病理诊断为糖尿病肾病；不包括发烧或有明显感染病灶,以及高尿酸患者；所有病例使用胰岛素控制血糖,利用血管紧张素拮抗剂和CCB类降压药控制血压,以及他汀类控制血脂,在行肾活检3月内未服用任何中药或者格列苯脲等降糖药。对照组为11例肾错构瘤患者,其肾组织标本均取自切除肾脏的远离肿瘤部分经病理检查为正常肾组织。
常规生化方法测定血清总胆固醇、低密度胆固醇、SCr、24h尿蛋白定量,并根据公式计算eGFR值。利用免疫荧光和免疫组化检测患者肾小管P2X4、NLRP3、IL-1β、 IL-18的表达情况。并分析肾小管上皮细胞P2X4、NLRP3和尿IL-1β、IL-18水平之间的相关性。
2.2细胞培养
HK-2细胞,作为一种肾小管上皮细胞株,培养于含胎牛血清10%的低糖DMEM培养基。HK-2细胞在无血清DMEM中静止12h,1)分别以35mM D-glucose或5mM D-glucose+30mM甘露醇作用于HK-2细胞0、12、24、48、72小时；2)分别培养于正常糖浓度,高糖浓度,高甘露醇浓度,作用48小时。分别利用apyrase (eATP水解酶),suramin(P2受体拮抗剂),TNP-ATP(P2X受体拮抗剂),或者5-BDBD(P2X4受体拮抗剂)和35mM D-glucose共同作用于HK-2细胞48h。
利用ATP荧光素检测试剂盒检测细胞上清液中ATP的表达水平。利用PBFI-AM检测细胞内钾离子浓度,利用Fluo-3/AM检测细胞内钙离子浓度。利用western blot检测细胞内NLRP3、细胞上清液中成熟的caspase-1和IL-1β的表达,利用ELISA检测细胞上清液中IL-1β和IL-18的水平。
2.3细胞转染
分别以脂质体LipofectamineTM2000加对照Green-Fluorescein Conjugate对照siRNA、无荧光标记对照siRNA、或者P2X4siRNA,转染肾小管上皮细胞24h后,进行高糖刺激48h。
利用PBFI-AM检测细胞内钾离子浓度,利用Fluo-3/AM检测细胞内钙离子浓度。利用western blot检测细胞内NLRP3、细胞上清液中成熟的caspase-1和IL-1β的表达,利用ELISA检测细胞上清液中IL-1β和IL-18的水平。
3.结果：
3.1肾小管上皮细胞P2X4表达与DN肾间质炎症相关
2型糖尿病肾病患者肾小管上皮细胞P2X4和NLRP3表达水平明显升高。P2X4和NLRP3的免疫组化表达评分分别和尿IL-1β、IL-18水平均呈正相关关系。免疫荧光结果显示P2X4的表达分别和NLRP3、IL-1β、IL-18蛋白呈共定位现象。
3.2高糖依赖细胞外ATP激活NLRP3炎性体
高糖刺激下HK-2细胞内NLRP3的表达、细胞上清液中成熟的caspase-1和IL-1p的表达、以及细胞分泌IL-1β、几-18和ATP的水平呈明显剂量和时间依赖性升高。Apyrase消耗掉细胞外ATP,能完全阻断高糖上调NLRP3、成熟的caspase-1、IL-1β和总IL-1p、IL-18的表达。
3.3高糖引起HK-2细胞的ATP-P2X4信号轴活化
高糖刺激导致HK-2细胞内钾离子浓度浓度明显下降,钙离子浓度明显上升。Apyrase能够明显抑制高糖诱导的HK-2细胞内钾离子浓度的降低和钙离子浓度的升高。Suramin、TNP-ATP、5-BDBD均能显著抑制高糖引起细胞内钾离子浓度的降低。TNP-ATP、5-BDBD均能抑制高糖引起细胞内钙离子浓度的升高。
3.4P2X4受体介导高糖激活NLRP3炎性体
Suramin、TNP-ATP以及5-BDBD均能够明显抑制高糖上调NLRP3、成熟的caspase-1、IL-1β和总IL-1β、IL-18的表达。P2X4siRNA转染能够明显抑制的高糖引起的细胞内低钾高钙,以及NLRP3、成熟的caspase-1、IL-1β和总IL-1p、IL-18表达的升高。
4.结论：
ATP-P2X4轴通过介导高糖依赖细胞外ATP激活NLRP3炎性体,调控IL-1家族细胞因子的成熟和分泌,在引发糖尿病肾病肾间质炎症反应中发挥着关键作用。
1. Background
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease Tubulointerstitial inflammation is crucial in promoting the development and progression of DN. Interleukin-1(IL-1) family cytokines have an initiating role in early stages of inflammation in DN. They have direct relationships with many chronic complications of diabetes. Pro-IL-1β and pro-IL-18, the precursor molecules of IL-1family cytokines, rely on caspase-1shearing action to exert their biological effects. The NOD-like receptor3(NLRP3) inflammasome, the intracellular receptor of dangerous related molecular pattern (DAMP), can activate caspase-1, regulate IL-1β and IL-18maturation and secretion, and trigger the inflammation of metabolic diseases such as diabetes, obesity, and gout. NLRP3knock-out mice are protected from renal tubule damage and renal interstitial inflammation in kidney unilateral ureteral occlusion (UUO) and ischemia-reperfusion models. The NLRP3inflammasome is activated in kidney tissue of streptozotocin-induced diabetic rats, and both quercetin and allopurinol can significantly reduce renal tissue inflammation and improve renal function by blocking NLRP3inflammasome activation. These data show that the NLRP3inflammasome plays a key role in the process of kidney sterile inflammation. However, the mechanism of NLRP3inflammasome activation in DN is still not clear.
Activated purinergic P2X receptors mediate endogenous DAMPs such as adenosine triphosphate (ATP), biglycan, and amyloid protein, activate the NLRP3inflammasome, and regulate aseptic inflammation in hypersensitivity, acute pancreatitis and cancer. P2X receptors are ligand-gated ion channel receptors in the P2family. There are seven subtypes (P2X1-7), which are expressed in the kidney with the exception of P2X3. Renal tubule epithelial cells mainly express P2X4and P2X6. ATP is a wide range P2X receptor agonist. Increased extracellular ATP (eATP) induced by hyperglycemia, can activate P2X7receptor of glomerular mesangial cell, and up-regulate TGF-β and extracellular matrix expression in diabetes. Hyperglycemia can also rely on eATP, and cause retinal cell caspase-1activation and IL-1β secretion. The role of P2X4in diabetic nephropathy is still undefined. The purpose of this study is to investigate the role of ATP-P2X4signaling in NLRP3inflammasome activation and renal interstitial inflammation of DN and provide theoretical foundation for analyzing the pathogenesis of renal inflammation and finding new treatments for DN.
2. Methods
2.1Patients
A total of45patients with type2diabetic nephropathy were recruited for this study from the Department of Nephrology in Daping Hospital from January1,2011to June1,2012. The enrollment criteria were as follows:patients were40-70years old with a history of type2diabetes;24h urine protein was above150mg; renal biopsy pathology led to a diagnosis of diabetic nephropathy; and no fever with obvious infection lesions or high uric acid. All patients used insulin to control blood glucose, angiotensin antagonist and CCB to control blood pressure, and statins to control lipids. Patients abstained from traditional Chinese medicine or sulfonylureas for three months after renal biopsy. Normal kidney tissues from nephrectomies of renal hamartoma were collected to be used in the control group.
Serum total cholesterol, LDL cholesterol, SCr,24h urinary protein excretion was measured by biochemical analysis. P2X4, NLRP3, IL-1β and IL-18expression in renal tubule was detected by immunofluorescence and immunohistochemistry. The relationship of P2X4, NLRP3and urinary IL-1β and IL-18were analysed.
2.2Cell culture
HK-2cells were cultured in Dulbecco's modified Eagle's medium with low glucose. The cells were seeded at1.5x106cells/10cm diameter dish for2-3days at37℃in a humidified atmosphere containing5%CO2. HK-2cells were grown in media with normal glucose concentration, or high glucose concentration, or high mannitol concentrations for48h. HK-2cells were incubated in media with high glucose (35mM,48h) with and without apyrase, P2receptor antagonist suramin, P2X receptor antagonist TNP-ATP and P2X4selective antagonist5-BDBD.
ATP levels were determined using an ATP luciferase-based bioluminescence assay kit in a luminometer. Intracellular K+concentration was measured by PBFI-AM. Cytosolic free Ca2+was indicated by Fluo-3/AM. NLRP3protein expression, cleavage of caspase-1and IL-1β were analyzed by Western Blot. Release of IL-1β and IL-18were detected by ELISA.
2.3P2X4siRNA transfection
Transfection control cells were transfected with siRNA for unrelated genes or control siRNA, while experimental cells were transfected with siRNA directed against P2X4, with all transfections utilizing Lipofectamine2000according to the manufacturer's instructions. Cells incubated with Lipofectamine2000were also used as a negative control. P2X4knockdown was confirmed by Western blot and quantitative reverse transcription-PCR (qRT-PCR).
3. Results
3.1P2X4expression related with renal interstitial inflammation in DN
P2X4and NLRP3expression was upregulated in tubular epithelial cells in patients with type2DN. P2X4immunostaining score, as well as NLRP3immunostaining score, was positively correlated with urine IL-1β and IL-18levels. P2X4expression was co-localized with NLRP3, IL-1β, and IL-18expression in the DN group.
3.2High glucose-induced NLRP3inflammasome activation is extracellular ATP-dependent
After stimulation of high glucose, NLRP3expression, cleavage of caspase-1and IL-1β, and release of ATP, IL-1β and IL-18were enhanced in a dose and time dependent way. Apyrase significantly inhibited NLRP3expression, cleavage of caspase-1and IL-1β, and release of IL-1β and IL-18caused by high glucose.
3.3High glucose caused ATP-P2X4signaling activation
High glucose cause intracellular calcium concentration increase, and potassium ion concentration reduce. Apyrase significantly inhibited potassium concentration reduction and calcium concentration increase under high glucose condition. Suramin, TNP-ATP,5-BDBD can significantly inhibit potassium concentration reducing caused by high glucose. Moreover, TNP-ATP,5-BDBD can restrain intracellular calcium concentration increasing cause by high glucose as well.
3.4P2X4receptor mediated NLRP3inflammasome activation caused by high glucose
Suramin, TNP-ATP and5-BDBD all obviously inhibited NLRP3expression, cleavage of caspase-land IL-1β, and release of IL-1β and IL-18with high glucose stimulus. P2X4gene silencing inhibited intracellular potassium efflux and extracellular calcium influx induced by high glucose. The increases in NLRP3expression, cleavage of caspase-land IL-1β, and secretion of IL-1β and IL-18were similarly blunted.
4. Conclusion
ATP-P2X4signaling mediates high glucose-induced activation of the NLRP3inflammasome, regulates IL-1family cytokine secretion, and plays a privotal role in the development of tubulointerstitial inflammation in diabetic nephropathy.
引文
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