scholarly journals Thioredoxin-Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Ye Da Xiao ◽  
Ya Yi Huang ◽  
Hua Xin Wang ◽  
Yang Wu ◽  
Yan Leng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Daily Injection ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Caspase 1 ◽  
Ischemic Acute Kidney Injury ◽  
The Impact

Kidney in diabetic state is more sensitive to ischemic acute kidney injury (AKI). However, the underlying mechanisms remain unclear. Herein, we examined the impact of diabetes mellitus on thioredoxin-interacting protein (TXNIP) expression and whether mediated NLRP3 activation was associated with renal ischemia/reperfusion- (I/R-) induced AKI. In an in vivo model, streptozotocin-induced diabetic rats showed higher susceptibility to I/R injury with increased TXNIP expression, which was significantly attenuated by resveratrol (RES) treatment (10 mg/kg intraperitoneal daily injection for 7 consecutive days prior to I/R induction). RES treatment significantly inhibited TXNIP binding to NLRP3 in diabetic rats subjected to renal I/R injury. Furthermore, RES treatment significantly reduced cleaved caspase-1 expression and production of IL-1β and IL-18. In an in vitro study using cultured human kidney proximal tubular cell (HK-2 cells) in high glucose condition (HG, 30 mM) subjected to hypoxia/reoxygenation (H/R), HG combined H/R (HH/R) stimulated TXNIP expression which was accompanied by increased NLRP3 expression, ROS generation, caspase-1 activity and IL-1β levels, and aggravated HK-2 cells apoptosis. All these changes were significantly attenuated by TXNIP RNAi and RES treatment. In conclusion, our results demonstrate that TXNIP-mediated NLRP3 activation through oxidative stress is a key signaling mechanism in the susceptibility to AKI in diabetic models.

scholarly journals Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice

2009 ◽  
Vol 296 (3) ◽  
pp. F535-F542 ◽  
Author(s):  
Zhibin He ◽  
Belda Dursun ◽  
Dong-Jin Oh ◽  
Lawrence Lu ◽  
Sarah Faubel ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Adoptive Transfer ◽  
Kidney Injury ◽  
Peritoneal Macrophages ◽  
Raw 264.7 Cells ◽  
Wild Type ◽  
Interleukin 18 ◽  
Caspase 1 ◽  
Outer Stripe ◽  
Ischemic Acute Kidney Injury

We previously reported in ischemic acute kidney injury (AKI) in mice that caspase-1-mediated production of interleukin-18 (IL-18) is pathogenic and that macrophage depletion by liposome-encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, reversed the functional protection against AKI in both LEC-treated wild-type and caspase-1 −/− mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild-type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice, and IL-18 −/− mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild-type as well as IL-18 BP Tg and IL-18 −/− mice reversed the functional protection against AKI in LEC-treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage-depleted wild-type and caspase-1 −/− mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage-depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.

The impact of Caspase-1 deletion on apoptosis and acute kidney injury in a murine transplant model

2021 ◽  
pp. 110039
Author(s):  
Swati Jain ◽  
Robert Plenter ◽  
Rahkola Jeremy ◽  
Trevor Nydam ◽  
Ronald G. Gill ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Caspase 1 ◽  
The Impact ◽  
Transplant Model

scholarly journals The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110374
Author(s):  
Hai-Peng Fan ◽  
Zhi-Xia Zhu ◽  
Jia-Jun Xu ◽  
Yu-Tang Li ◽  
Chun-Wen Guo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Susceptibility ◽  
Kidney Injury ◽  
In Vivo Model ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Downstream Target ◽  
Renal Tubular

Objective This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). Methods A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. Results CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. Conclusions CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.

scholarly journals Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-Induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model

2020 ◽  
Vol 21 (11) ◽  
pp. 3983 ◽  
Author(s):  
Islam N. Mohamed ◽  
Nader Sheibani ◽  
Azza B. El-Remessy
Keyword(s):  
Adhesion Molecules ◽  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
High Fat ◽  
Barrier Dysfunction ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
The Impact

We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.

scholarly journals STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

2021 ◽  
Author(s):  
Yan-Yan Heng ◽  
Xiao-Yan Zhang ◽  
Fei-Fei Wang ◽  
Peng-Fei Zhang ◽  
wei wei
Keyword(s):  
Dna Damage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Vascular Endothelial ◽  
Urine Protein ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Abstract Background: Glomerular endothelial cell (GEC) injury is one of the crucial causes of diabetic kidney disease (DKD). Endothelial progenitor cell (EPC) is the essential mechanism of vascular endothelial repair, which damages by diabetic pathology. Sodium Tanshinone Sulfonate ⅡA (STS) is known to protect endothelium, but the mechanism and the role in DKD need to be studied. Methods: EPC was treated with high glucose (HG), and thioredoxin interacting protein (TXNIP), NLR family pyrin domain containing 3 (NLRP3) inflammasome, DNA damage, proliferation, differentiation and senescence were detected; STS and EPC were intravenous injected into diabetic nude mice, the urine protein quantitation and urine protein/creatinine were detected; the Dil-labeled EPC was traced and the expression of TXNIP, caspase-1 (p20), p21, Ki67, CD31 were detected by fluorescence co-location in glomerulus.Results: We found that STS inhibited HG-induced TXNIP expression and NLRP3 inflammasome activation, catalase (CAT) inactivation, DNA damage, senescence； STS restored EPC proliferation and differentiation functions; advanced glycation end products (AGEs) produced in HG treated EPC supernatant, the receptor of AGE (RAGE) blocking inhibited TXNIP expression and NLRP3 inflammasome activation, which mimicked by STS. STS protected EPC functions in diabetic glomerular and enhanced EPC renal function amelioration. Conclusions: We concluded that STS watched CAT activity to prevent HG-induced EPC DNA damage, proliferation, differentiation dysfunction, accelerated senescence by inhibiting the RAGE-TXNIP-NLRP3 inflammasome-caspase-1 pathway.

Abstract 15397: Enhanced AKAP12/GRAVIN Expression Leads to Myocardial Injury by Disrupting Angiogenic Signals Related to HSP/Thioredoxin-1/VEGF Cascade in Type I Diabetic Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vaithinathan Selvaraju ◽  
Sumanth C Suresh ◽  
Mahesh Thirunavukkarasu ◽  
J.Alexander Palesty ◽  
Juan A Sanchez ◽  
...  
Keyword(s):  
Heart Function ◽  
Immunoblot Analysis ◽  
Diabetic Rats ◽  
Border Zone ◽  
Type I ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Downstream Target ◽  
Thioredoxin 1 ◽  
The Impact

Background: Our earlier studies showed that AKAP12 and Thioredoxin-Interacting Protein (TXNIP) interfere with HSPA12B-induced angiogenic signaling in rat myocardium. HSPA12B appears to play an essential role in myocardial angiogenesis, which is impaired during diabetes. This study explores the impact of HSPA12B overexpression on heart function, neovascularization, and downstream target proteins, AKAP12, Thioredoxin-1 (Trx-1) and VEGF, in non-diabetic and diabetic animals following myocardial infarction (MI). Methods: Rats were divided into 6 groups: 1) Non-Diabetic Sham (NDS), 2) Non-Diabetic LacZ MI (NDLZMI), 3) Non-Diabetic HSPA12B MI (NDHSPMI), 4) Diabetic Sham (DS), 5) Diabetic LacZ MI (DLZMI), 6) Diabetic HSPA12B MI (DHSPMI). Ad.LacZ/Ad.HSPA12B was administered intramyocardially at 4 sites around the infarct border zone in NDLZMI/DiaLZMI or NDHSPMI/DiaHSPMI animals immediately after permanent LAD ligation. Results: Co-immunoprecipitation followed by immunoblot analysis showed significant increase in HSPA12B/AKAP12 association in diabetic group suggesting that diabetes impairs HSPA12B availability triggering impairment of angiogenesis. This result was also confirmed by docking analysis (insilico models). Trx-1 activity (1.73 fold) along with HSPA12B and VEGF expression was increased in DHSPMI and NDHSPMI compared to respective controls. Both AKAP12 (1.31 fold) and TXNIP (2.22 fold) appeared to be down-regulated in HSPA12B-treated groups compared to controls. Echocardiography demonstrated increased fractional shortening and ejection fraction 4 weeks post-MI in DHSPMI-treated rats compared to DLZMI. Increased capillary and arteriolar density in DHSPMI compared to DLZMI was obesrved by morphometric analysis. In addition Picrosirius red staining documented decreased fibrosis in DHSPMI vs. DLZMI myocardium. Conclusion: Therefore overexpression of HSPA12B enhances neovascularization and cardiac function following MI in diabetic animals by down-regulating Trx-1/TXNIP and HSPA12B/AKAP12 association, resulting in increased HSPA12B, Trx-1 and VEGF. These findings support a role for HSPA12B gene therapy in mitigating the morbid expression of ischemic heart disease in the setting of diabetes.

scholarly journals Does deeper hypothermia reduce the risk of acute kidney injury after circulatory arrest for aortic arch surgery?

2021 ◽  
Author(s):  
Andrew M Vekstein ◽  
Babtunde A Yerokun ◽  
Oliver K Jawitz ◽  
Julie W Doberne ◽  
Jatin Anand ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Circulatory Arrest ◽  
Aortic Surgery ◽  
Multivariable Analysis ◽  
Kidney Injury ◽  
Deep Hypothermia ◽  
Moderate Hypothermia ◽  
Bladder Temperature ◽  
Increased Risk ◽  
The Impact

Abstract OBJECTIVES The impact of hypothermic circulatory arrest (HCA) temperature on postoperative acute kidney injury (AKI) has not been evaluated. This study examined the association between circulatory arrest temperatures and AKI in patients undergoing proximal aortic surgery with HCA. METHODS A total of 759 consecutive patients who underwent proximal aortic surgery (ascending ± valve ± root) including arch replacement requiring HCA between July 2005 and December 2016 were identified from a prospectively maintained institutional aortic surgery database. The primary outcome was AKI as defined by Risk, Injury, Failure, Loss, End Stage Renal Disease (ESRD) criteria. The association between minimum nasopharyngeal (NP) and bladder temperatures during HCA and postoperative AKI was assessed, adjusting for patient-level factors using multivariable logistic regression. RESULTS A total of 85% (n = 645) of patients underwent deep hypothermia (14.1–20.0°C), 11% (n = 83) low-moderate hypothermia (20.1–24.0°C) and 4% (n = 31) high-moderate hypothermia (24.1–28.0°C) as classified by NP temperature. When analysed by bladder temperature, 59% (n = 447) underwent deep hypothermia, 22% (n = 170) low-moderate, 16% (n = 118) high-moderate and 3% mild (n = 24) (28.1–34.0°C) hypothermia. The median systemic circulatory arrest time was 17 min. The incidence of AKI did not differ between hypothermia groups, whether analysed using minimum NP or bladder temperature. In the multivariable analysis, the association between degree of hypothermia and AKI remained non-significant whether analysed as a categorical variable (hypothermia group) or as a continuous variable (minimum NP or bladder temperature) (all P > 0.05). CONCLUSIONS In patients undergoing proximal aortic surgery including arch replacement requiring HCA, degree of systemic hypothermia was not associated with the risk of AKI. These data suggest that moderate hypothermia does not confer increased risk of AKI for patients requiring circulatory arrest, although additional prospective data are needed.

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