缺血预处理对肝脏缺血再灌注损伤保护作用的研究

1986年,Murry等[1]发现短暂的缺血和再灌注能使心肌耐受后续长期的缺血,这与以往认为缺血再灌注次数越多、损伤越严重的看法相矛盾,由此提出了缺血预处理的概念(ischemiapreconditioning,IP),即预先反复短暂的缺血再灌注,诱导机体产生一种内源性的保护机制,以增强机体对随后长时间缺血再灌注的耐受性,减轻脏器损伤的现象。随后众多研究发现IP不仅可在心脏中发生,同样也可发生在肝脏、骨骼肌、脑、小肠、肺、肾脏等组织器官。1997年,Peralta等[2]发现肝脏经IP后,阻滞其血供90min再灌注,能明显降低血液中各种转氨酶含量,随后Yin等[3]报道…     

山莨菪碱对大鼠肝脏缺血再灌注损伤保护作用的实验研究

目的 探索山莨菪碱对大鼠肝脏缺血再灌注损伤的保护作用。方法 选雄性Wistar大鼠160只,分为正常对照组、缺血再灌注组、生理盐水组和山莨菪碱组,观察了肝脏缺血60分钟及再灌注1、3、6、12及24小时后血浆内皮素－1（ET－1）、透明质酸（HA）和谷丙转氨酶（ALT）含量变化及肝组织病理学变化。结果 肝脏缺血再灌注后,血浆ET－1、HA和ALT含量均明显增高,同时肝脏瘀血很明显,肝脏缺血再灌注前用山莨菪碱后,血浆HA和ALT含量明显降低,同时肝组织瘀血减轻。结论 山莨菪碱可改善再灌注后的肝脏微循环障碍,对大鼠肝脏缺血再灌注损伤有保护作用。     

前列腺素E1对大鼠肝脏缺血再灌注损伤的保护作用

摘要：目的:探讨肝脏缺血后前列腺素E1（PGE1）对再灌注损伤的保护作用及其可能机制。方法:建立大鼠70％的肝脏缺血再灌注模型。将24只健康雄性SD大鼠随机分为假手术（S）组、缺血再灌注（I/R）组及PGE1处理组，各组于缺血45 min再灌注1h后取静脉血，观察血清肝酶、超氧化物歧化酶（SOD）、丙二醛（MDA）、髓过氧化物酶（MPO）的含量变化，并行肝组织病理学检查。结果:与S组比较，I/R组与PGE1组血清ALT，AST，LDH显著升高，SOD活性明显降低，MDA和MPO含量均明显升高（P＜0.01）。PGE1组与I/R组相比，前者血清ALT，AST，LDH降低（P＜0.01），肝形态学异常变化明显减轻，血清SOD活性升高，MDA和MPO含量降低（P＜0.01）。结论:PGE1对大鼠肝脏I/R损伤有明显的保护作用；其作用机制部分可能是提高组织的抗氧化能力和减轻中性粒细胞的聚集。     

预缺血对肝脏缺血再灌注损伤的保护作用

已有较多的实验证明,预缺血处理对多种缺血再灌注器官有保护作用.本文综述了预缺血对缺血再灌注肝脏的保护作用及其机理.     

前列腺素E1和重组人生长激素对肝缺血-再灌注损伤的保护作用

我们用兔肝脏缺血 再灌注损伤及肝切除模型 ,采用前列腺素Ｅ1 (ＰＧＥ1 )和重组人生长激素 (ｒｈＧＨ)单独及联合用药的方法 ,探索减轻肝脏缺血 再灌注损伤的新方法。一、材料和方法1 .动物及分组 :健康大耳白兔 48只 ,3 %戊巴比妥钠 (30ｍｇ/ｋｇ体重 )静脉注入麻醉 ,阻断第一肝门 40ｍｉｎ时切除左肝外叶 ,45ｍｉｎ后解除阻断。实验动物随机等分为 4组 :Ａ组 (对照组 ,1 2只) ,缺血前后静脉滴注生理盐水 (ＮＳ)0 .5ｍｌ·ｋｇ- 1 ·ｍｉｎ- 1 ;Ｂ组 (ＰＧＥ1 组 ,1 2只) ,缺血前后静脉滴注ＰＧＥ1 0 .5μｇ·ｋｇ- 1 ·ｍｉｎ- 1 ;Ｃ组 (…     

大鼠常温下肝缺血再灌注前后门静脉输注前列腺素Ｅ１的肝保护作用

我们自1998年3月至1999年通过建立经门静脉插管注药的动物模型,对比经门静脉及外周静脉注药的效果,现将结果报告如下。材料和方法1.实验对象:健康ＳＤ大鼠18只,雌雄不限。体重300～350ｇ之间。术前12ｈ禁食。2.实验分组及方法:大鼠腹腔内注射1%戊巴比妥钠溶液30ｍｇ/ｋｇ麻醉。上腹部正中切口开腹,分离门静脉主干及左右分支,经肠系膜上静脉分支插入肝素化小导管,进入左门静脉主干内,用小血管夹夹闭肝叶左支以阻断左肝血供,造成左肝缺血,45ｍｉｎ后松开小血管夹,恢复血流,形成再灌注。对照组分别于左肝血流阻断前和再灌注开始时,从门静脉插管…     

脂质体携载前列腺素E1对扩张皮瓣缺血-再灌注损伤的影响

目的 观察脂质体携载前列腺素E1 (liposome prostaglandin E1,Lipo PGE1)对扩张皮瓣缺血-再灌注损伤的影响.方法 采用中国小型猪背部扩张随意皮瓣缺血再灌注损伤模型,实验分为两组:实验组(Lipo PGE1干预组)及对照组.在其背部形成8 cm×2 cm扩张皮瓣,通过不同时间远端扩张皮瓣组织匀浆中髓过氧化酶(MPO)及丙二醛(MDA)含量测定,以及皮瓣微血管密度(MVD)、皮瓣存活率和皮温测定,观察Lipo PGE1对皮瓣成活的影响.结果 实验组皮瓣存活率明显高于对照组(P＜0.05),术后两组MPO及MDA含量差异有统计学意义(P＜0.05),实验组明显低于对照组.两组MVD含量差异无统计学意义(P＞0.05).实验组用药后皮肤温度明显升高.结论 应用Lipo PGE1可以减轻缺血-再灌注损伤,提高扩张皮瓣存活率.     

预缺血对肝脏缺血再灌注损伤的保护作用

已有较多的实验证明,预缺血处理对多种缺血再灌注器官有保护作用.本文综述了预缺血对缺血再灌注肝脏的保护作用及其机理.     

前列腺素E1对大鼠睾丸缺血再灌注后的影响

目的初步探讨前列腺素E1（PGE1）对睾丸缺血再灌注后的功能保护作用及其可能的分子机制。方法建立大鼠睾丸缺血再灌注的病理模型（以扭转后复位为例）。随机分成A、B、C3组，每组12只。A、B、C组分别为对照、治疗和非治疗组。所有大鼠在手术45d后处死，取睾丸组织，肉眼观察其形态，称其重量（计算脏器系数），放入固定液以备行常规HE染色后镜下观察睾丸的病理改变，并在图像分析系统下测量精曲小管的直径，并对所有结果利用SPSS软件系统进行统计学处理。结果（1）肉眼观察形态：B组与A组相比差别不明显，B组与C组比较差别显著;（2）镜下观察形态：B组与A组相比差别不明显，B组与C组比较差别显著;（3）脏器系数比较：B组与A组差别无显著性（P〉0.05）B组与C组差别显著（P〈0.05）;（4）精曲小管直径比较：B组与A组差别无显著性（P〉0.05）B组与C组差别显著（P〈0.05）。结论PGE1有减轻缺血再灌注导致的病理改变，可以运用于临床上治疗睾丸扭转复位后和睾丸移植术后，对睾丸功能恢复有明显促进作用。     

缺血预处理对大鼠肝脏缺血再灌注损伤保护作用机制的研究

目的　探讨缺血预处理 (IPC)保护作用的发生机制。方法　建立大鼠部分肝脏热缺血再灌注模型。IPC采用肝脏缺血 10min ,再灌注 10min。结果　IPC后肝组织中腺苷和NO水平明显升高 ,与对照组相比差异显著 (P <0 0 1) ,但IPC前应用腺苷A2 受体拮抗剂后NO的升高被抑制 (P<0 0 1)。缺血再灌注 (I/R) 2h后血清中TNF α、AST、ALT、LDH及W/D水平和假手术组相比明显增加 ,而IL 10含量降低 (P <0 0 1) ;IPC、I/R前加入腺苷、IPC前应用腺苷A1受体拮抗剂显著地降低TNF α释放和AST、ALT、LDH及W /D水平 ,提高IL 10含量 ,与I/R组相比差异显著 (P <0 0 1) ;但IPC前应用腺苷A2 受体拮抗剂 (IPC +A2 antag)和NO合成酶抑制剂NAME并没有能像IPC组那样有效降低TNF α、AST、ALT、LDH及W /D的水平 ,提高IL 10的含量 (P <0 0 1) ;而IPC前给IPC+A2 antag组提供NO前体精氨酸又获得和IPC组同样的结果 (P >0 0 5 )。结论　IPC引起细胞外腺苷水平升高 ,腺苷A2 受体活化 ,介导了NO合成增加 ,最终通过抑制效应器TNF α的释放、增加IL 10的合成来实现对缺血组织的保护作用。     

Clotrimazole Protects the Liver Against Normothermic Ischemia-Reperfusion Injury in Rats

Objective

To investigate the possible antiapoptotic prosurvival role of the pregnane X receptor (PXR) in hepatic ischemia-reperfusion injury in rats using clotrimazole (CTZ), a strong PXR transactivator.

Materials and Methods

Male Sprague-Dawley rats were divided into 3 groups of 6 each: sham-treated, control, and CTZ-treated animals. Control and CTZ-treated animals were subjected to 30 minutes of normothermic ischemia of the whole liver followed by 6 hours of reperfusion. The animals were then killed, and the liver was excised and blood samples collected.

Results

Clotrimazole induced a significant increase in expression of the CYP3A gene, indicating PXR transactivation, whereas expression of the antiapoptotic Bcl-xL gene was not increased. Serum concentrations of aspartate aminotransaminase and alanine aminotransaminase were lower in CTZ-treated animals than in control animals (difference not significant). Levels of poly(adenosine diphosphate–ribose) polymerase, a caspase-3 substrate, remained significantly higher in the CTZ-treated group compared with controls (P < .05). Clotrimazole increased the expression of phospho-p 44/42 extracellular signal-regulated kinase 1,2 (P < .05). The gene expression of the heat shock proteins 27, 70 and 90 was significantly lower in CTZ-treated animals than in controls (P < .05).

Conclusion

Clotrimazole-mediated PXR transactivation protects the liver against ischemia-reperfusion apoptosis in rats. Phospho-p 44/42 extracellular signal-regulated kinase 1,2 is activated, whereas gene expression of heat shock proteins 27, 70, and 90 is downregulated by induction of PXR.     

Delayed Ischemic Preconditioning Protects Against Liver Ischemia-Reperfusion Injury In Vivo

Objectives

Ischemic preconditioning (IP) affords resistance to liver ischemia-reperfusion (IR) injury, providing an early phase of protection. Development of delayed IP against IR injury was assessed using partial IR in rat liver.

Methods

The IP manuver (10 minutes of ischemia and up to 72 hours of reperfusion) was induced before 1 hour of ischemia and 20 hours of reperfusion. At the end of the reperfusion period, blood and liver samples were analyzed for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), haptoglobin and tumor necrosis factor-α (TNF-α) levels, hepatic histology, protein carbonyl and glutathione (GSH) contents as well as nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) DNA binding.

Results

The IP manuver significantly increased protein carbonyl/GSH ratios (275%), serum ALT (42%), and AST (58%); these changes normalized after 12 hours. Serum AST, ALT, and LDH levels were significantly increased by IR (4-, 5.6-, and 7.0-fold, respectively), with significant changes in liver histology, protein carbonyl/GSH ratio (481% enhancement), and serum TNF-α (6.1-fold increase). Delayed IP in IR animals reduced serum AST (66%), ALT (57%), and LDH (90%) and liver GSH depletion (89%), with normalization of protein carbonyl content, serum TNF-α levels, and liver histology. Enhanced AP-1/NF-κB DNA binding ratios and diminished haptoglobin expression induced by IR were normalized by IP.

Conclusion

These data support that delayed IP suppresses IR-induced liver injury, oxidative stress, and TNF-α response, which coincide with recovery of IR-altered signaling functions represented by normal AP-1/NF-κB DNA binding ratios and acute phase responses.     

Activation of Sphingosine-1-Phosphate 1 Receptor in the Proximal Tubule Protects Against Ischemia-Reperfusion Injury

Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P₁R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P₁R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS- or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P₁R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P₁Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P₁Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P₁R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P₁Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury.Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which is associated with prolonged hospitalization and high morbidity and mortality. The pathogenesis of AKI is complex and involves direct effects on vascular endothelial cells, tubule cells, and immune cells.^1,2 Kidney tubular epithelial cells express both TLR-2 and TLR-4, which are thought to respond to endogenous “danger signals” to initiate AKI.³ These danger signals activate immune cells, leading to inflammation induced by cytokines, chemokines, and classic innate effector immune cells, such as neutrophils and macrophages.Lymphocytes are important mediators of experimental IRI in the kidney as well as other organs.^4–6 Lymphocytes contribute to the pathogenesis of IRI, and their absence, such as in mice deficient in B (μMT)⁷ or T cells (nu/nu)^6,8 or both (Rag-1 knockout [KO]),⁶ confers protection from kidney IRI.Sphingosine-1-phosphate (S1P), a sphingolipid that is produced by phosphorylation of sphingosine by sphingosine kinases, is the natural ligand for a family of five G protein–coupled receptors (GPCRs; S1P_{1 to 5}Rs) and evokes diverse cellular signaling responses.^9–11 Phosphorylated FTY720 (FTY720-P), the active form of the drug, is a nonselective agonist that activates S1P_{1,3 to 5}Rs.^12,13 The protective efficacy of FTY720 via direct activation of S1P₁Rs results in a reversible redistribution of lymphocytes (B and T cells) from the circulation to secondary lymph tissue and thus away from sites of inflammation.^12,14 Furthermore, activation of S1P₁Rs elicits various tissue-protective effects in normal and disease states. More importantly, S1P₁R is critical in mouse vascular development¹⁵ (i.e., global S1P₁R gene disruption is embryonically lethal at midgestation as a result of a failure of vascular maturation^15,16). FTY720-P–treated cultured oligodendrocyte progenitor cells are protected from apoptotic cell death through activation of mitogen-activated protein kinase/extracellular regulated kinase (MEK/ERK) and phosphatidylinositol-3-kinase (PI3K)/Akt signaling.¹⁷ The downstream MEK/ERK and PI3K/Akt signaling pathways, which are activated by various GPCRs, have been implicated in promoting cell survival under various conditions along with pertussis toxin–sensitive coupling of S1P₁R activation.^18,19We and others have demonstrated that selective activation of the S1P₁Rs with S1P₁R agonists reduces kidney IRI^20–22; however, it is not known whether the tissue-protective effects of these S1P₁R agonists are mediated by the canonical effect of S1P₁R agonists to induce lymphopenia or by stimulating S1P₁Rs on other target tissues or both. Previously, we demonstrated that mice treated with FTY720 were protected from kidney IRI; VPC44116, a selective S1P₁R antagonist, reversed the protective effects of FTY720 but did not reverse the lymphopenia induced by FTY720.²⁰ This observation led us to hypothesize that S1P₁R agonists may have additional direct effects on kidney resident cells independent of lymphocytes to reduce injury after kidney IRI.This study explored the mechanisms involved in S1P₁R-mediated tissue protection from IRI in a mouse model of AKI. We demonstrated that S1P₁R agonists protect kidneys from IRI, independent of B and T lymphocytes, through direct activation of S1P₁Rs expressed on renal proximal tubule epithelial cells (PTECs) and, further, that the S1P₁R agonist protective effect requires PTEC S1P₁Rs as demonstrated by using Cre-floxed transgenic mice. Furthermore, S1P₁R agonists directly block apoptosis and induce cell survival pathways via activation of the Akt and/or mitogen-activated protein kinase (MAPK) pathways.     

Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver

ABSTRACT

Background: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. Methods: Severe hepatic steatosis was performed by 12–14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. Results: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%).Conclusions: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.     

Diannexin, a Novel Annexin V Homodimer, Protects Rat Liver Transplants Against Cold Ischemia-Reperfusion Injury

Ischemia/reperfusion injury (IRI) remains an important problem in clinical transplantation. Following ischemia, phosphatidylserine (PS) translocates to surfaces of endothelial cells (ECs) and promotes the early attachment of leukocytes/platelets, impairing microvascular blood flow. Diannexin, a 73 KD homodimer of human annexin V, binds to PS, prevents attachment of leukocytes/platelets to EC, and maintains sinusoidal blood flow. This study analyzes whether Diannexin treatment can prevent cold IRI in liver transplantation. Rat livers were stored at 4 degrees C in UW solution for 24 h, and then transplanted orthotopically (OLT) into syngeneic recipients. Diannexin (200 microg/kg) was infused into: (i) donor livers after recovering and before reperfusion, (ii) OLT recipients at reperfusion and day +2. Controls consisted of untreated OLTs. Both Diannexin regimens increased OLT survival from 40% to 100%, depressed sALT levels, and decreased hepatic histological injury. Diannexin treatment decreased TNF-alpha, IL-1beta, IP-10 expression, diminished expression of P-selectin, endothelial ICAM-1, and attenuated OLT infiltration by macrophages, CD4 cells and PMNs. Diannexin increased expression of HO-1/Bcl-2/Bcl-xl, and reduced Caspase-3/TUNEL+ apoptotic cells. Thus, by modulating leukocyte/platelet trafficking and EC activation in OLTs, Diannexin suppressed vascular inflammatory responses and decreased apoptosis. Diannexin deserves further exploration as a novel agent to attenuate IRI, and thereby improve OLT function/increase organ donor pool.     

Effects of Apocynin on Liver Ischemia-Reperfusion Injury in Rats

ObjectiveIschemia-reperfusion (IR) injury is associated with various clinical conditions, such as myocardial infarction, shock, and surgery under vascular occlusion. We aimed to investigate the protective and therapeutic effects of apocynin (AP) on liver injury induced by IR in an in vivo rat model.MethodsThirty-two rats were randomly divided into 4 experimental groups with n = 8 in each group: sham, IR, AP, and IR + AP. AP (20 mg/kg) was intraperitoneally administered to rats in the AP and IR + AP groups for 30 minutes before 60 minutes of ischemia and followed by 60 minutes of reperfusion. All rats were killed on the same day to evaluate tissue levels of oxidants and antioxidants (catalase, malondialdehyde, myeloperoxidase, superoxidedismutase (SOD), and total glutathione).ResultsIR decreased SOD levels in IR group when compared with the sham group. AP supplementation to IR group significantly ameliorated SOD levels (P < .05). Also, IR caused elevation of myeloperoxidase production when compared with the sham group, whereas AP treatment prevented these hazardous effects (P < .05). However, plasma total glutathione, catalase, and malondialdehyde levels did not differ between the AP + IR and the IR rats.ConclusionThe main finding of the present study was that AP may be protective against liver IR injury. Our results suggested that AP pretreatment suppressed oxidative stress and increased antioxidant levels in an rat model of liver IR.     

Rosiglitazone Protects Against Cyclosporine-Induced Pancreatic and Renal Injury in Rats

Rosiglitazone (RGTZ) has protective effect against various types of injury. This study was performed to evaluate the effect of RGTZ on pancreatic and renal injury caused by cyclosporine (CsA). CsA (15 mg/kg) and RGTZ (3 mg/kg) were administered alone and together to the rats for 28 days. The effect of RGTZ on CsA-induced pancreatic injury was evaluated by intraperitoneal glucose tolerance test (IPGTT), plasma insulin concentrations and pancreatic beta-cell morphology. The effect of RGTZ on CsA-induced renal injury was evaluated by assessing renal function and pathology; mediators of inflammation and fibrosis such as angiotensin II (AngII), osteopontin (OPN) and transforming growth factor-beta1 (TGF-beta1) and apoptotic cell death. Four weeks of CsA treatment caused diabetes, renal dysfunction, typical pathologic lesions (arteriolopathy, interstitial fibrosis and inflammatory cells infiltration) and apoptotic cell death. RGTZ treatment decreased blood glucose concentration, increased plasma insulin concentration and preserved pancreatic beta islet mass. RGTZ treatment improved renal function and histopathology. Pro-inflammatory and pro-fibrotic molecules such as AngII, OPN and TGF-beta1, and apoptotic cell death also decreased with RGTZ treatment. These data suggest that RGTZ has a protective effect against CsA-induced pancreatic and renal injury.     

L-Carnitine Protects Against Cyclosporine-Induced Pancreatic and Renal Injury in Rats

Background

L-carnitine has protective effects against various types of injury. This study was designed to evaluate the beneficial effects of L-carnitine on pancreatic and renal injuries caused by cyclosporine (CsA).

Methods

Rats maintained on a low sodium diet were given vehicle (olive oil, 1 mL/kg/d), CsA (15 mg/kg/d), L-carnitine (50 or 200 mg/kg/d), or a combination of CsA and L-carnitine for 4 weeks. The impact of L-carnitine on pancreatic injury was assessed by blood glucose levels, plasma insulin concentrations, and hemoglobulin A1c (HbA1c). In addition, the protective effects of L-carnitine against CsA-induced kidney injury were evaluated in terms of renal function, histopathology (inflammatory cell influx and tubulointerstitial fibrosis), oxidative stress (8-hydroxy 2′-deoxyguanosine, 8-OHdG), transforming growth factor-betal (TGF-β1), apoptosis (caspase-3), and autophagy (LC3-II).

Results

CsA treatment caused diabetes, renal dysfunction, tubulointerstitial inflammation (ED-1-positive cells), and fibrosis, which were accompanied by an increase in 8-OHdG production and upregulation of TGF-β1, caspase-3, and LC3-II. Concomitant administration of L-carnitine increased plasma insulin concentrations, decreasing plasma glucose and HbA1c levels. In the kidney, L-carnitine induced dose-dependent improvement of renal function, inflammation, and fibrosis in parallel with suppression of the expression of TGF-β1 and 8-OHdG. Furthermore, the administration of L-carnitine at a high dose inhibited the expression of caspase-3 and LC3-II.

Conclusion

These findings suggest that L-carnitine has a protective effect against CsA-induced pancreatic and renal injuries.