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Hamid Rabb - One of the best experts on this subject based on the ideXlab platform.
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early exposure to germs modifies Kidney damage and inflammation after experimental Ischemia reperfusion injury
American Journal of Physiology-renal Physiology, 2009Co-Authors: Hye Ryoun Jang, Maria Teresa Gandolfo, Shailesh Satpute, Lorraine C Racusen, Hamid RabbAbstract:Kidney Ischemia-reperfusion injury (IRI) is, in part, mediated by immune and inflammatory factors. Since microbial stimuli are known to alter immune and inflammatory responses, we hypothesized that differences in perinatal microbial status would modify renal injury following IRI. We performed bilateral renal IRI on 6-wk-old germ-free and control mice and studied the effects on Kidney lymphocyte trafficking, cytokines, function, and structure. Compared with control mice, normal Kidneys of germ-free mice exhibited more NKT cells and lower IL-4 levels. PostIschemia, more CD8 T cells trafficked into postischemic Kidneys of germ-free mice compared with control mice. Renal structural injury and functional decline following IRI were more severe in germ-free mice compared with control mice. When germ-free mice were conventionalized with the addition of bacteria to their diet, the extent of renal injury after IRI became equivalent to age-matched control mice, with similar numbers and phenotypes of T cells and NKT cells, as well as cytokine expression in both normal Kidneys and postischemic Kidneys of conventionalized germ-free mice and age-matched control mice. Thus microbial stimuli influence the phenotype of renal lymphocytes and the expression of cytokines of normal Kidneys and also modulate the outcome of IRI.
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the role for t cell repertoire antigen specific interactions in experimental Kidney Ischemia reperfusion injury
Journal of Immunology, 2009Co-Authors: Shailesh R Satpute, Hye Ryoun Jang, Maria Teresa Gandolfo, Lorraine C Racusen, Manchang Liu, Jong Myun Park, Patricia Agreda, Hamid RabbAbstract:T cells have been implicated in the early pathogenesis of Ischemia reperfusion injury (IRI) of Kidney, liver, lung, and brain. It is not known whether Ag-TCR engagement followed by Ag-specific T cell activation participates in IRI. T cell-deficient nu/nu mice are moderately resistant to renal IRI, which can be reversed upon reconstitution with syngeneic T cells. In this study, we found that nu/nu mice reconstituted with DO11.10 T cells, limited in their TCR repertoire, have significantly less Kidney dysfunction and tubular injury after renal IRI compared with that in nu/nu mice reconstituted with wild-type T cells having a diverse TCR repertoire. CD4 + T cells infiltrating ischemic Kidneys of nu/nu mice reconstituted with DO11.10 T cells exhibited lower IFN-γ production than that of wild-type controls. Frequency of regulatory T cells in Kidneys of these mice was similar in both DO11.10 T cells and wild-type T cell recipient groups. DO11.10 mice immunized with OVA-CFA had significantly worse Kidney function at 24 h after Ischemia than those immunized with CFA alone. Thus, without T cell activation, diverse TCR repertoire was important for renal IRI in naive mice. However, once T cells were activated in an Ag-specific manner through TCR in DO11.10 mice, a restricted TCR repertoire no longer limited the extent of Kidney injury. Thus, both TCR repertoire-dependent and -independent factors mediate T cell functions in Kidney IRI.
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the innate immune response in ischemic acute Kidney injury
Clinical Immunology, 2009Co-Authors: Hye Ryoun Jang, Hamid RabbAbstract:Kidney Ischemia reperfusion injury is a major cause of morbidity in both allograft and native Kidneys. Ischemia reperfusion-induced acute Kidney injury is characterized by early, alloantigen-independent inflammation. Major components of the innate immune system are activated and participate in the pathogenesis of acute Kidney injury, plus prime the allograft Kidney for rejection. Soluble members of innate immunity implicated in acute Kidney injury include the complement system, cytokines, and chemokines. Toll-like receptors (TLRs) are also important contributors. Effector cells that participate in acute Kidney injury include the classic innate immune cells, neutrophils and macrophages. Recent data has unexpectedly identified lymphocytes as participants of early acute Kidney injury responses. In this review, we will focus on immune mediators that participate in the pathogenesis of ischemic acute Kidney injury.
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the local and systemic inflammatory transcriptome after acute Kidney injury
Journal of The American Society of Nephrology, 2008Co-Authors: Dmitry N Grigoryev, Chris Cheadle, Kathleen C Barnes, Heitham T Hassoun, Manchang Liu, Hamid RabbAbstract:Studies in humans and animal models have demonstrated that acute Kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the Kidney and lung. In a murine model of ischemic AKI, prominent global transcriptomic changes and histologic injury in both Kidney and lung tissues were identified. These changes were evident at both early (6 h) and late (36 h) timepoints after 60-min bilateral Kidney Ischemia and were more prominent than similar timepoints after sham surgery or 30 min of Ischemia. The inflammatory transcriptome (109 genes) of both organs changed with marked similarity, including the innate immunity genes Cd14, Socs3, Saa3, Lcn2, and Il1r2. Functional genomic analysis of these genes suggested that IL-10 and IL-6 signaling was involved in the distant effects of local inflammation, and this was supported by increased serum levels of IL-10 and IL-6 after Ischemia-reperfusion. In summary, this is the first comprehensive analysis of concomitant inflammation-associated transcriptional changes in the Kidney and a remote organ during AKI. Functional genomic analysis identified potential mediators that connect local and systemic inflammation, suggesting that this type of analysis may be a useful discovery tool for novel biomarkers and therapeutic drug development.
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ischemic acute Kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy
American Journal of Physiology-renal Physiology, 2007Co-Authors: Heitham T Hassoun, Chris Cheadle, Dmitry N Grigoryev, Mihaela L Lie, Manchang Liu, Rubin M Tuder, Hamid RabbAbstract:Acute Kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury. Experiments in rodents have shown that Kidney Ischemia-reperfusion ...
Mark D Okusa - One of the best experts on this subject based on the ideXlab platform.
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vagus nerve stimulation mediates protection from Kidney Ischemia reperfusion injury through α7nachr splenocytes
Journal of Clinical Investigation, 2016Co-Authors: Tsuyoshi Inoue, Patrice G. Guyenet, Liping Huang, Diane L Rosin, Sunsang J Sung, Stefan Moscalu, Jakub Jankowski, Hong Ye, Mark D OkusaAbstract:The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The inflammatory reflex referred to as the cholinergic antiinflammatory pathway regulates innate and adaptive immunity, and modulation of this reflex by vagus nerve stimulation (VNS) is effective in various inflammatory disease models, such as rheumatoid arthritis and inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates Kidney Ischemia-reperfusion injury (IRI), which promotes the release of proinflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute Kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes.
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autocrine adenosine signaling promotes regulatory t cell mediated renal protection
Journal of The American Society of Nephrology, 2012Co-Authors: Gilbert R Kinsey, Liping Huang, Peter I Lobo, Katarzyna Jaworska, Konstantine Khutsishvili, David A Becker, Mark D OkusaAbstract:Regulatory T cells (Tregs) suppress the innate inflammation associated with Kidney Ischemia-reperfusion injury (IRI), but the mechanism is not well understood. Tregs express CD73, the final enzyme involved in the production of extracellular adenosine, and activation of the adenosine 2A receptor (A2AR) on immune cells suppresses inflammation and preserves Kidney function after IRI. We hypothesized that Treg-generated adenosine is required to block innate immune responses in Kidney IRI and that the Treg-generated adenosine would signal through A2ARs on inflammatory cells and, in an autocrine manner, on Tregs themselves. We found that adoptively transferred wild-type Tregs protected wild-type mice from Kidney IRI, but the absence of adenosine generation (CD73-deficient Tregs) or adenosine responsiveness (A2AR-deficient Tregs) led to inhibition of Treg function. Pharmacologic stimulation of A2AR before adoptive transfer augmented the ability of wild-type and CD73-deficient Tregs to suppress Kidney IRI. Microarray analysis and flow cytometry revealed that A2AR activation enhanced surface PD-1 expression on Tregs in the absence of any other activation signal. Treatment of Tregs with a PD-1 blocking antibody before adoptive transfer reversed their protective effects, even if pretreated with an A2AR agonist. Taken together, these results demonstrate that the simultaneous ability to generate and respond to adenosine is required for Tregs to suppress innate immune responses in IRI through a PD-1–dependent mechanism.
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activation of sphingosine 1 phosphate 1 receptor in the proximal tubule protects against Ischemia reperfusion injury
Journal of The American Society of Nephrology, 2010Co-Authors: Amandeep Bajwa, Liping Huang, Diane L Rosin, Volker H Haase, Krishna R Dondeti, Timothy L Macdonald, Kevin R Lynch, Mark D OkusaAbstract: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.
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macrophages dendritic cells and Kidney Ischemia reperfusion injury
Seminars in Nephrology, 2010Co-Authors: Mark D OkusaAbstract:Dendritic cells and macrophages are critical early initiators of innate immunity in the Kidney and orchestrate inflammation subsequent to Ischemia-reperfusion injury. They are the most abundant leukocytes present in the Kidney, and they represent a heterogeneous population of cells that are capable of inducing sterile inflammation after reperfusion directly through the production of proinflammatory cytokines and other soluble inflammatory mediators or indirectly through activation of effector T lymphocytes and natural killer T cells. In addition, recent studies have indicated that Kidney and immune cell micro-RNAs control gene expression and have the ability to regulate the initial inflammatory response to injury. Although dendritic cells and macrophages contribute to both innate and adaptive immunity and to injury and repair, this review focuses on the initial innate response to Kidney Ischemia-reperfusion injury.
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il 17 produced by neutrophils regulates ifn γ mediated neutrophil migration in mouse Kidney Ischemia reperfusion injury
Journal of Clinical Investigation, 2010Co-Authors: Liping Huang, Amy L Vergis, Amandeep Bajwa, Vivek Narayan, Robert M Strieter, Diane L Rosin, Mark D OkusaAbstract:The IL-23/IL-17 and IL-12/IFN-γ cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute Kidney Ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-γ signaling pathways and promotes Kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute Kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for Kidney IRI in mice. Activation of the IL-12/IFN-γ pathway and NKT cells by administering α-galactosylceramide–primed bone marrow–derived DCs increased IFN-γ production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-γ production in either Il17a–/– or Il17r–/– mice, which suggested that IL-17 signaling was proximal to IFN-γ signaling. This was confirmed by the finding that IFN-γ administration reversed the protection seen in Il17a–/– mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng–/– mice. These results demonstrate that the innate immune component of Kidney IRI requires dual activation of the IL-12/IFN-γ and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-γ. These mechanisms might contribute to reperfusion injury in other organs.
Kwon Moo Park - One of the best experts on this subject based on the ideXlab platform.
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Oxidative stress following acute Kidney injury causes disruption of lung cell cilia and their release into the bronchoaveolar lavage fluid and lung injury, which are exacerbated by Idh2 deletion
'Elsevier BV', 2021Co-Authors: Yong Kwon Han, Ji Su Kim, Gwan Beom Lee, Jae Hang Lim, Kwon Moo ParkAbstract:Acute Kidney injury (AKI) induces distant organ injury, which is a serious concern in patients with AKI. Recent studies have demonstrated that distant organ injury is associated with oxidative stress of organ and damage of cilium, an axoneme-based cellular organelle. However, the role of oxidative stress and cilia damage in AKI-induced lung injury remains to be defined. Here, we investigated whether AKI-induced lung injury is associated with mitochondrial oxidative stress and cilia disruption in lung cells. AKI was induced in isocitrate dehydrogenase 2 (Idh2, a mitochondrial antioxidant enzyme)-deleted (Idh2−/−) and wild-type (Idh2+/+) mice by Kidney Ischemia-reperfusion (IR). A group of mice were treated with Mito-TEMPO, a mitochondria-specific antioxidant. Kidney IR caused lung injuries, including alveolar septal thickening, alveolar damage, and neutrophil accumulation in the lung, and increased protein concentration and total cell number in bronchoalveolar lavage fluid (BALF). In addition, Kidney IR caused fragmentation of lung epithelial cell cilia and the release of fragments into BALF. Kidney IR also increased the production of superoxide, lipid peroxidation, and mitochondrial and nuclei DNA oxidation in lungs and decreased IDH2 expression. Lung oxidative stress and injury relied on the degree of Kidney injury. Idh2 deletion exacerbated Kidney IR-induced lung injuries. Treatment with Mito-TEMPO attenuated Kidney IR-induced lung injuries, with greater attenuation in Idh2−/− than Idh2+/+ mice. Our data demonstrate that AKI induces the disruption of cilia and damages cells via oxidative stress in lung epithelial cells, which leads to the release of disrupted ciliary fragments into BALF
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mitochondrial nadp dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after Kidney Ischemia reperfusion injury
Journal of The American Society of Nephrology, 2017Co-Authors: Sangjun Han, Jee In Kim, Heeseong Jang, Mi Ra Noh, Jinu Kim, Min Jung Kong, Jeenwoo Park, Kwon Moo ParkAbstract:Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance. Ischemia-reperfusion (I/R) is one of most common causes of AKI. I/R disrupts the mitochondrial redox balance, resulting in oxidative damage to mitochondria and cells. Here, we investigated the role of IDH2 in I/R-induced AKI. I/R injury in mice led to the inactivation of IDH2 in Kidney tubule cells. Idh2 gene deletion exacerbated the I/R-induced increase in plasma creatinine and BUN levels and the histologic evidence of tubule injury, and augmented the reduction of NADPH levels and the increase in oxidative stress observed in the Kidney after I/R. Furthermore, Idh2 gene deletion exacerbated I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in Kidney tubule cells. In cultured mouse Kidney proximal tubule cells, Idh2 gene downregulation enhanced the mitochondrial damage and apoptosis induced by treatment with hydrogen peroxide. This study demonstrates that Idh2 gene deletion exacerbates mitochondrial damage and tubular cell death via increased oxidative stress, suggesting that IDH2 is an important mitochondrial antioxidant enzyme that protects cells from I/R insult.
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gender specific role of hdac11 in Kidney Ischemia and reperfusion induced pai 1 expression and injury
American Journal of Physiology-renal Physiology, 2013Co-Authors: Jee In Kim, Kyongjin Jung, Heeseong Jang, Kwon Moo ParkAbstract:Male gender and the male hormone testosterone increase susceptibility to Kidney Ischemia and reperfusion (I/R) injury, which is associated with inflammatory responses. Possible involvement of histone deacetylase (HDAC) in inflammatory responses has been suggested. We investigated the gender-specific role of HDACs in plasminogen activator inhibitor type-1 (PAI-1) expression and I/R injury. PAI-1 inhibition protected the Kidney from I/R-induced inflammation and functional loss. Among HDACs, only HDAC11 negatively regulated PAI-1 expression in I/R-subjected Kidney gender specifically and lipopolysaccharide (LPS)-stimulated mouse monocytes/macrophages. HDAC11 gene silencing increased PAI-1 expression. Chromatin immunoprecipitation assay confirmed binding of HDAC11 to the promoter region of PAI-1 and then release by I/R insult or LPS treatment. I/R-induced HDAC11 release was inhibited by orchiectomy and reversed by dihydrotestosterone treatment. Release of HDAC11 increased acetylation of histone H3. In conclusion, male gender and male hormones accelerate I/R-induced decreases in expression and binding of HDAC11, resulting in an increase in PAI-1 expression. These data provide important insight into gender dimorphism offering HDAC11 as a novel target for I/R injury.
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orchiectomy reduces susceptibility to renal ischemic injury a role for heat shock proteins
Biochemical and Biophysical Research Communications, 2005Co-Authors: Kwon Moo Park, Hee Jung Cho, Joseph V BonventreAbstract:In previous studies we demonstrated that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in Kidney Ischemia/reperfusion (I/R) injury. Although molecular chaperones such as heat shock proteins (HSPs) have been implicated as protective agents in the pathophysiology of I/R injury, their roles in gender differences in susceptibility to renal I/R injury remain to be defined. Here we demonstrate that orchiectomy increases the basal and post-ischemic expression of HSP-27 in Kidney tubular epithelial cells, but not HSP-72, glucose-regulated protein (GRP)-78 or GRP-94 expression. Orchiectomy prevents the disruption of the actin cytoskeleton and renal functional disorders induced by I/R, when compared with intact male mice or orchiectomized mice treated with dihydrotestosterone, a non-aromatizable isoform of testosterone. Thus, the protection afforded by orchiectomy is associated with increased expression of HSP-27, a heat shock protein important for maintenance of actin cytoskeletal integrity. These findings indicate that testosterone inhibits the heat shock response and may provide a new paradigm for design of therapies for I/R injury.
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inducible nitric oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse Kidney
Journal of Biological Chemistry, 2003Co-Authors: Kwon Moo Park, Jee In Kim, Jiyeon Byun, Cornelis Kramers, Paul L Huang, Joseph V BonventreAbstract:Ischemic preconditioning renders the mouse Kidney resistant to subsequent Ischemia. Understanding the mechanisms responsible for ischemic preconditioning is important for formulating therapeutic strategies aimed at mimicking protective mechanisms. We report that the resistance afforded by 30 min of bilateral Kidney Ischemia persists for 12 weeks after preconditioning. The protection is reflected by improved postischemic renal function, reduced leukocyte infiltration, reduced postischemic disruption of the actin cytoskeleton, and reduced postischemic expression of Kidney injury molecule-1 (Kim-1). The protection is observed in both BALB/c and C57BL/6J strains of mice. Thirty minutes of prior Ischemia increases the expression of inducible nitric-oxide synthase (iNOS) and endothelial NOS (eNOS) and the expression of heat shock protein (HSP)-25 and is associated with increased interstitial expression of alpha-smooth muscle actin (alpha-SMA), an indication of long term postischemic sequelae. Treatment with Nomega-nitro-l-arginine (l-NNA), an inhibitor of NO synthesis, increases Kidney susceptibility to Ischemia. Gene deletion of iNOS increases Kidney susceptibility to Ischemia, whereas gene deletion of eNOS has no effect. Pharmacological inhibition of NOS by l-NNA or l-N6-(1-iminoethyl) lysine (l-NIL, a specific inhibitor of iNOS) mitigates the Kidney protection afforded by 30 min of ischemic preconditioning. Fifteen minutes of prior ischemic preconditioning, which does not result in the disruption of the actin cytoskeleton, impairment of renal function, increased interstitial alpha-SMA, or increased iNOS or eNOS expression, but does increase HSP-25 expression, partially protects the Kidney from Ischemia on day 8 via a mechanism that is not abolished by l-NIL treatment. Thus, iNOS is responsible for a significant component of the long term protection afforded the Kidney by ischemic preconditioning, which results in persistent renal interstitial disease, but does not explain the preconditioning seen with shorter periods of Ischemia.
Joseph V Bonventre - One of the best experts on this subject based on the ideXlab platform.
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orchiectomy reduces susceptibility to renal ischemic injury a role for heat shock proteins
Biochemical and Biophysical Research Communications, 2005Co-Authors: Kwon Moo Park, Hee Jung Cho, Joseph V BonventreAbstract:In previous studies we demonstrated that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in Kidney Ischemia/reperfusion (I/R) injury. Although molecular chaperones such as heat shock proteins (HSPs) have been implicated as protective agents in the pathophysiology of I/R injury, their roles in gender differences in susceptibility to renal I/R injury remain to be defined. Here we demonstrate that orchiectomy increases the basal and post-ischemic expression of HSP-27 in Kidney tubular epithelial cells, but not HSP-72, glucose-regulated protein (GRP)-78 or GRP-94 expression. Orchiectomy prevents the disruption of the actin cytoskeleton and renal functional disorders induced by I/R, when compared with intact male mice or orchiectomized mice treated with dihydrotestosterone, a non-aromatizable isoform of testosterone. Thus, the protection afforded by orchiectomy is associated with increased expression of HSP-27, a heat shock protein important for maintenance of actin cytoskeletal integrity. These findings indicate that testosterone inhibits the heat shock response and may provide a new paradigm for design of therapies for I/R injury.
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inducible nitric oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse Kidney
Journal of Biological Chemistry, 2003Co-Authors: Kwon Moo Park, Jee In Kim, Jiyeon Byun, Cornelis Kramers, Paul L Huang, Joseph V BonventreAbstract:Ischemic preconditioning renders the mouse Kidney resistant to subsequent Ischemia. Understanding the mechanisms responsible for ischemic preconditioning is important for formulating therapeutic strategies aimed at mimicking protective mechanisms. We report that the resistance afforded by 30 min of bilateral Kidney Ischemia persists for 12 weeks after preconditioning. The protection is reflected by improved postischemic renal function, reduced leukocyte infiltration, reduced postischemic disruption of the actin cytoskeleton, and reduced postischemic expression of Kidney injury molecule-1 (Kim-1). The protection is observed in both BALB/c and C57BL/6J strains of mice. Thirty minutes of prior Ischemia increases the expression of inducible nitric-oxide synthase (iNOS) and endothelial NOS (eNOS) and the expression of heat shock protein (HSP)-25 and is associated with increased interstitial expression of alpha-smooth muscle actin (alpha-SMA), an indication of long term postischemic sequelae. Treatment with Nomega-nitro-l-arginine (l-NNA), an inhibitor of NO synthesis, increases Kidney susceptibility to Ischemia. Gene deletion of iNOS increases Kidney susceptibility to Ischemia, whereas gene deletion of eNOS has no effect. Pharmacological inhibition of NOS by l-NNA or l-N6-(1-iminoethyl) lysine (l-NIL, a specific inhibitor of iNOS) mitigates the Kidney protection afforded by 30 min of ischemic preconditioning. Fifteen minutes of prior ischemic preconditioning, which does not result in the disruption of the actin cytoskeleton, impairment of renal function, increased interstitial alpha-SMA, or increased iNOS or eNOS expression, but does increase HSP-25 expression, partially protects the Kidney from Ischemia on day 8 via a mechanism that is not abolished by l-NIL treatment. Thus, iNOS is responsible for a significant component of the long term protection afforded the Kidney by ischemic preconditioning, which results in persistent renal interstitial disease, but does not explain the preconditioning seen with shorter periods of Ischemia.
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prevention of Kidney Ischemia reperfusion induced functional injury and jnk p38 and mapk kinase activation by remote ischemic pretreatment
Journal of Biological Chemistry, 2001Co-Authors: Kwon Moo Park, Ang Chen, Joseph V BonventreAbstract:MAPK activities, including JNK, p38, and ERK, are markedly enhanced after Ischemia in vivo and chemical anoxia in vitro. The relative extent of JNK, p38, or ERK activation has been proposed to determine cell fate after injury. A mouse model was established in which prior exposure to Ischemia protected against a second ischemic insult imposed 8 or 15 days later. In contrast to what was observed after 30 min of bilateral Ischemia, when a second period of Ischemia of 30- or 35-min duration was imposed 8 days later, there was no subsequent increase in plasma creatinine, decrease in glomerular filtration rate, or increase in fractional excretion of sodium. A shorter period of prior Ischemia (15 min) was partially protective against subsequent ischemic injury 8 days later. Unilateral Ischemia was also protective against a subsequent ischemic insult to the same Kidney, revealing that systemic uremia is not necessary for protection. The Ischemia-related activation of JNK and p38 and outer medullary vascular congestion were markedly mitigated by prior exposure to Ischemia, whereas preconditioning had no effect on post-ischemic activation of ERK1/2. The phosphorylation of MKK7, MKK4, and MKK3/6, upstream activators of JNK and p38, was markedly reduced by ischemic preconditioning, whereas the post-ischemic phosphorylation of MEK1/2, the upstream activator of ERK1/2, was unaffected by preconditioning. Pre- and post-ischemic HSP-25 levels were much higher in the preconditioned Kidney. In summary, post-ischemic JNK and p38 (but not ERK1/2) activation was markedly reduced in a model of Kidney ischemic preconditioning that was established in the mouse. The reduction in JNK and p38 activation can be accounted for by reduced activation of upstream MAPK kinases. The post-ischemic activation patterns of MAPKs may explain the remarkable protection against ischemic injury observed in this model.
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characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease htra and is regulated by Kidney Ischemia
Journal of Biological Chemistry, 2000Co-Authors: Lucia Faccio, Ang Chen, Joseph V Bonventre, Carlo Fusco, Stefano Martinotti, Antonis S ZervosAbstract:Abstract We report the isolation and characterization of a cDNA encoding the novel mammalian serine protease Omi. Omi protein consists of 458 amino acids and has homology to bacterial HtrA endoprotease, which acts as a chaperone at low temperatures and as a proteolytic enzyme that removes denatured or damaged substrates at elevated temperatures. The carboxyl terminus of Omi has extensive homology to a mammalian protein called L56 (human HtrA), but unlike L56, which is secreted, Omi is localized in the endoplasmic reticulum. Omi has several novel putative protein-protein interaction motifs, as well as a PDZ domain and a Src homology 3-binding domain. Omi mRNA is expressed ubiquitously, and the gene is localized on human chromosome 2p12. Omi interacts with Mxi2, an alternatively spliced form of the p38 stress-activated kinase. Omi protein, when made in a heterologous system, shows proteolytic activity against a nonspecific substrate β-casein. The proteolytic activity of Omi is markedly up-regulated in the mouse Kidney following Ischemia/reperfusion.
Thomas H Lee - One of the best experts on this subject based on the ideXlab platform.
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peptidyl arginine deiminase 4 exacerbates ischemic aki by finding nemo
American Journal of Physiology-renal Physiology, 2019Co-Authors: May M Rabadi, Sangjun Han, Mihwa Kim, Vivette D Dagati, Thomas H LeeAbstract:Peptidyl arginine deiminase-4 (PAD4) catalyzes the conversion of peptidylarginine residues to peptidylcitrulline. We have previously shown that Kidney Ischemia-reperfusion (I/R) injury increases re...
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peptidyl arginine deiminase 4 activation exacerbates Kidney Ischemia reperfusion injury
American Journal of Physiology-renal Physiology, 2014Co-Authors: Ahrom Ham, May M Rabadi, Mihwa Kim, Vivette D Dagati, Kevin M Brown, Thomas H LeeAbstract:Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute Kidney injury (AKI) by exacerbating the inflammatory response after renal Ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse Kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse Kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.
