Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal ischemia-reperfusion (IR) injury is a major clinical problem without effective therapy. We recently reported that volatile anesthetics protect against renal IR injury, in part, via their anti-inflammatory properties. In this study, we demonstrate the anti-inflammatory and antinecrotic effects of sevoflurane in cultured kidney proximal tubule cells and probed the mechanisms of sevoflurane-induced renal cellular protection. To mimic inflammation, human kidney proximal tubule (HK-2) cells were treated with tumor necrosis factor-alpha (TNF-alpha; 25 ng/ml) in the presence or absence of sevoflurane. In addition, we studied the effects of sevoflurane pretreatment on hydrogen peroxide (H2O2)-induced necrotic cell death in HK-2 or porcine proximal tubule (LLC-PK1) cells. We demonstrate that sevoflurane suppressed proinflammatory effects of TNF-alpha evidenced by attenuated upregulation of proinflammatory cytokine mRNA (TNF-alpha, MCP-1) and ICAM-1 protein and reduced nuclear translocation of the proinflammatory transcription factors NF-kappaB and AP-1. Sevoflurane reduced necrotic cell death induced with H2O2 in HK-2 cells as well as in LLC-PK1 cells. Sevoflurane treatment resulted in phosphorylation of prosurvival kinases, ERK and Akt, and increased de novo HSP-70 protein synthesis without affecting the synthesis of HSP-27 or HSP-32. We conclude that sevoflurane has direct anti-inflammatory and antinecrotic effects in vitro in a renal cell type particularly sensitive to injury following IR injury. These mechanisms may, in part, account for volatile anesthetics' protective effects against renal IR injury.
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PMID:Anti-inflammatory and antinecrotic effects of the volatile anesthetic sevoflurane in kidney proximal tubule cells. 1647 75

The complement system is one of the important mediators of renal ischemia-reperfusion injury (IRI). We hypothesized that efficient silencing of C3, which is the central component on which all complement activation pathways converge, could be achieved using small interfering RNA (siRNA), and that this would result in overall inhibition of complement activation, thereby preventing IRI in kidneys. A series of experiments was conducted, using a mouse model of IRI and vector-delivered C3-specific siRNA. We demonstrated the following: (1) renal expression of C3 increases as a result of IRI; (2) by incorporation into a pRNAT U6.1 vector, siRNA can be delivered to renal cells in vivo; (3) systemically delivered siRNA is effective in reducing the expression of C3 in an experimentally induced mouse kidney model of IRI; (4) similarly, siRNA reduces complement-mediated IRI-related effects, both in terms of renal injury (as evidenced by renal function and histopathology examination) and mouse mortality and (5) silencing the production of C3 diminishes in vivo production of TNF-alpha. This study implies that siRNA represents a novel approach to preventing IRI in kidneys and might be used in a variety of clinical settings, including transplantation and acute tubular necrosis.
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PMID:Preventing renal ischemia-reperfusion injury using small interfering RNA by targeting complement 3 gene. 1679 25

T and B lymphocytes have been implicated in the pathogenesis of renal ischemia reperfusion injury (IRI). The trafficking of lymphocytes into kidneys during IRI has been postulated to underlie this effect, but has not been rigorously studied. We therefore characterized the lymphocyte populations infiltrating into mouse kidneys 3 and 24 h after renal IRI. Immunohistochemistry and flow cytometry staining of kidney lymphocytes showed increased trafficking of CD3+ T cells and CD19+ B cells in both sham-operated and IRI mice 3 h after renal IRI. In the IRI mice, increased infiltration of NK1.1+ and CD4+ NK1.1+ cells compared with normal and sham-operated mice was observed 3 and 24 h after renal IRI, respectively. After 24 h of renal IRI, the decreased percentages of CD3+, CD19+, and NK1.1+ populations in the IRI mice compared with control groups were observed. Increased TNF-alpha and IFN-gamma production of kidney infiltration CD3+ T cells in IRI mice but not sham-operated mice was found. Unexpectedly, isolation and transfer of kidney-infiltrating lymphocytes 24 h after renal IRI into T cell-deficient mice reduced their functional and histological injury after renal IRI, suggesting that kidney-infiltrating lymphocytes could have a protective function. These quantitative, qualitative, and functional changes in kidney lymphocytes provide mechanistic insight into how lymphocytes modulate IRI, as well as demonstrating that abdominal surgery alone leads to lymphocyte changes in kidney.
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PMID:Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury. 1692 Sep 79

Renal tubular epithelial cells (TEC) die by apoptosis or necrosis in renal ischemia-reperfusion injury (IRI). Fas/Fas ligand-dependent fratricide is critical in TEC apoptosis, and Fas promotes renal IRI. Therefore, targeting Fas or caspase-8 may have therapeutic potential for renal injury in kidney transplant or failure. RNA silencing by short hairpin RNA (shRNA) is a novel strategy to down-regulate protein expression. Using this approach, silencing of Fas or caspase-8 by shRNA to prevent TEC apoptosis and IRI was evaluated. IRI was induced by renal artery clamping for 45 or 60 min at 32 degrees C in uninephrectomized C57BL/6 mice. Here, we showed that Fas or pro-caspase-8 expression was significantly knocked down in TEC by stable expression of shRNA, resulting in resistance to apoptosis induced by superoxide, IFN-gamma/TNF-alpha and anti-Fas antibody. Inferior vena cava delivery of pHEX-small interfering RNA targeting Fas or pro-caspase-8 resulted in protection of kidney from IRI, indicated by reduction of renal tubular injury (necrosis and apoptosis) and serum creatinine or blood urea nitrogen. Our data suggest that shRNA-based therapy targeting Fas and caspase-8 in renal cells can lead to protection of kidney from IRI. Attenuation of pro-apoptotic proteins using genetic manipulation strategies such as shRNA might represent a novel strategy to promote kidney allograft survival from rejection or failure.
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PMID:Increasing resistance of tubular epithelial cells to apoptosis by shRNA therapy ameliorates renal ischemia-reperfusion injury. 1697 Jul 99

Acute renal failure (ARF) is a frequent complication of sepsis and has a high mortality. Sepsis-induced ARF is known to be associated with significant impairment of tubular capacity. However, the pathogenesis of endotoxemic tubular dysfunction with failure of urine concentration is poorly understood. Urea plays an important role in the urinary concentrating mechanism and expression of the urea transporters UT-A1, UT-A2, UT-A3, UT-A4, and UT-B is essential for tubular urea reabsorption. The present study attempts to assess the regulation of renal urea transporters during severe inflammation in vivo. Lipopolysaccharide-(LPS)-injected mice presented with reduced glomerular filtration rate, fractional urea excretion, and inner medulla osmolality associated with a marked decrease in expression of all renal urea transporters. Similar alterations were observed after application of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, or IL-6. LPS-induced downregulation of urea transporters was not affected in knockout mice with deficient TNF-alpha, IL-receptor-1, IFN-gamma, or IL-6. Glucocorticoid treatment inhibited LPS-induced increases of tissue TNF-alpha, IL-1beta, IFN-gamma, or IL-6 concentration, diminished LPS-induced renal dysfunction, and attenuated the downregulation of renal urea transporters. Renal ischemia induced by renal artery clipping did not influence the expression of urea transporters. Our data demonstrate that renal urea transporters are downregulated by severe inflammation, which likely accounts for tubular dysfunction. Furthermore, they suggest that the downregulation of renal urea transporters during LPS-induced ARF is mediated by proinflammatory cytokines and is independent from renal ischemia because of sepsis-induced hypotension.
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PMID:Cytokine-mediated regulation of urea transporters during experimental endotoxemia. 1722 73

Sepsis-associated acute renal failure is characterized by decreased GFR and tubular dysfunction. The pathogenesis of endotoxemic tubular dysfunction with failure in urine concentration and increased fractional sodium excretion is poorly understood. This study investigated the regulation of renal sodium transporters during severe inflammation in vivo and in vitro. Injection of high-dosage LPS reduced BP and GFR, increased fractional sodium excretion, and strongly decreased the expression of Na(+)/H(+)-exchanger, renal outer medullary potassium channel, Na(+)-K(+)-2Cl(-) co-transporter, epithelial sodium channel, and Na(+)/K(+)-ATPase in mice. Also, injection of TNF-alpha, IL-1beta, or IFN-gamma decreased renal function and expression of renal sodium transporters. LPS-induced downregulation of sodium transporters was not affected in cytokine-knockout mice. However, supplementary glucocorticoid treatment, which inhibited LPS-induced increase of tissue cytokine concentrations, attenuated LPS-induced renal dysfunction and downregulation of tubular sodium transporters. Injection of low-dosage LPS increased renal tissue cytokines and downregulated renal sodium transporters without arterial hypotension. In vitro, in cortical collecting duct cells, cytokines also decreased expression of renal outer medullary potassium channel, epithelial sodium channel, and Na(+)/K(+)-ATPase. Renal hypoperfusion by renal artery clipping did not influence renal sodium transporter expression, in contrast to renal ischemia-reperfusion injury, which depressed transporter expression. These findings demonstrate downregulation of renal sodium transporters that likely accounts for tubular dysfunction during inflammation. These data suggest that alteration of renal sodium transporters during LPS-induced acute renal failure is mediated by cytokines rather than renal ischemia. However, in a complex in vivo model of severe inflammation, the possible presence and influence of renal hypoperfusion and reperfusion on the expression of renal sodium transporters cannot be completely excluded.
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PMID:Regulation of renal sodium transporters during severe inflammation. 1731 27

We have demonstrated that volatile anesthetics reduce inflammation after renal ischemia/reperfusion injury in vivo. As hyperactive uncontrolled inflammation can lead to mortality and morbidity during early sepsis, we questioned whether the volatile anesthetic isoflurane could reduce mortality and protect against sepsis induced renal and hepatic dysfunction. Mice were anesthetized with isoflurane or with pentobarbital and subjected to cecal ligation and puncture (CLP) to induce septic peritonitis. Mice were anesthetized for an additional 3 h after CLP with either isoflurane or pentobarbital. Renal and hepatic function was assessed 24 h later and survival after CLP was assessed for 7 days. To determine if isoflurane protects by reducing inflammation, we quantified renal tubular expression of pro-inflammatory (intercellular adhesion molecule 1, tumor necrosis factor alpha [TNF-alpha], and interleukin [IL] 1beta) messenger RNA with reverse transcriptase-polymerase chain reaction. We also measured the plasma levels of the pro-inflammatory cytokines TNF-alpha, keratinocyte-derived chemokine (KC), and IL-6 and an anti-inflammatory cytokine IL-10. Renal cortical apoptosis was also assessed 24 h after CLP. Twenty-four hours after the septic insult, isoflurane-treated mice had significantly improved renal and hepatic function compared with mice anesthetized with pentobarbital. Renal cortices of isoflurane-treated mice had significantly reduced expression of intercellular adhesion molecule 1, TNF-alpha, and IL-1beta messenger RNA and showed less apoptosis. Isoflurane-treated mice had lower plasma levels of TNF-alpha, KC, and IL-6. Isoflurane-anesthetized mice also had significantly prolonged and increased survival compared with pentobarbital-anesthetized mice. Therefore, isoflurane anesthesia conferred significant protection against renal and hepatic dysfunction and death after septic peritonitis and attenuated renal inflammation and apoptosis compared with pentobarbital anesthesia.
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PMID:Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis. 1741 19

Inflammation after renal ischemia-reperfusion (IR) injury is a major contributor to renal cell death. We previously demonstrated that several volatile anesthetics protect against renal IR injury and necrosis in rats in vivo. We subsequently showed that volatile anesthetics produced direct anti-inflammatory and anti-necrotic effects in cultured proximal tubule cells in vitro. In this study, we wanted to determine whether the volatile anesthetic isoflurane protects against renal IR injury by producing anti-inflammatory effects in mice. C57BL/6 mice subjected to renal IR under isoflurane anesthesia demonstrated improved renal function and reduced necrosis compared with mice subjected to renal IR under pentobarbital anesthesia. Mice subjected to renal IR under isoflurane anesthesia also showed a reduction in inflammation evidenced by a reduced renal influx of neutrophils and macrophages, reduced ICAM-1 expression, less upregulation of proinflammatory mRNAs (TNF-alpha, ICAM-1, KC, and IL-1beta) as well as reduced nuclear translocation of NF-kappaB 24 h after renal IR injury. Analysis of specific lymphocyte subset trafficking to the kidney using flow cytometry demonstrated that isoflurane anesthesia reduced intrarenal influx of CD3+, CD4+, CD8+, and NK1.1+ lymphocytes at 3 h after renal ischemia compared with pentobarbital anesthesia. However, only the differential reduction of NK1.1+ lymphocytes persisted 24 h after renal ischemia. Therefore, we conclude that isoflurane anesthesia significantly attenuated renal IR injury in mice by reducing inflammation and modulating leukocyte influx. In particular, neutrophil, macrophage, and NK1.1+ lymphocyte cell modulation may play a significant role in renal protection by isoflurane anesthesia.
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PMID:Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice. 1759 28

We previously demonstrated that several clinically utilized volatile anesthetics including sevoflurane protected against renal ischemia-reperfusion (IR) injury by reducing necrosis and inflammation in vivo. We also demonstrated that volatile anesthetics produced direct anti-necrotic and anti-inflammatory effects in cultured renal tubules via mechanisms involving the externalization of phosphatidylserine and subsequent release of transforming growth factor (TGF)-beta1. In this study, we tested the hypothesis that volatile anesthetic-mediated renal protection requires TGF-beta1 and SMAD3 signaling in vivo. We subjected TGF-beta1+/+, TGF-beta1+/-, SMAD3+/+, or SMAD3-/- mice to renal IR under anesthesia with pentobarbital sodium or with sevoflurane. Although TGF-beta1+/+ and SMAD3+/+ mice were significantly protected against renal IR injury under sevoflurane anesthesia with reduced necrosis and inflammation, TGF-beta1+/- mice and SMAD3-/- mice were not protected against renal IR with sevoflurane. Furthermore, a neutralizing TGF-beta1 antibody blocked renal protection with sevoflurane in TGF-beta1+/+ mice. Sevoflurane caused nuclear translocation of SMAD3 and reduced the TNF-alpha-induced nuclear translocation of NF-kappaB in primary cultures of proximal tubules from TGF-beta1+/+ but not in TGF-beta1+/- mice. Finally, sevoflurane protected against necrosis induced with hydrogen peroxide in primary cultures of proximal tubules from TGF-beta1+/+ mice or SMAD3+/+ mice but not in proximal tubules from TGF-beta1+/- or SMAD3-/- mice. Therefore, we demonstrate in this study that sevoflurane-mediated renal protection in vivo requires the TGF-beta1-->SMAD3 signaling pathway.
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PMID:Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta1 pathway. 1843 84

Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kynurenine and has a proapoptotic role in renal tubular epithelial cells (TEC) in response to IFN-gamma and TNF-alpha in vitro. TEC produce abundant amounts of IDO in vitro in response to inflammation but a pathological role for IDO in renal injury remains unknown. We investigated the role of IDO in a mouse model of renal ischemia-reperfusion injury (IRI). IRI was induced by clamping the renal pedicle of C57BL/6 mice for 45 min at 32 degrees C. Here, we demonstrate upregulation of IDO in renal tissue at 2 h after reperfusion which reached maximal levels at 24 h. Inhibition of IDO following IRI prevented the increase in serum creatinine observed in vehicle-treated mice (86.4 +/- 25 micromol/l, n = 11) compared with mice treated with 1-methyl-D-tryptophan, a specific inhibitor of IDO (33.7 +/- 8.7 micromol/l, n = 10, P = 0.031). The role of IDO in renal IRI was further supported by results in IDO-KO mice which maintained normal serum creatinine levels (32.5 +/- 2.0 micromol/l, n = 6) following IRI compared with wild-type mice (123 +/- 30 micromol/l, n = 9, P = 0.008). Our data suggest that attenuation of IDO expression within the kidney may represent a novel strategy to reduce renal injury as a result of ischemia reperfusion.
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PMID:Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury. 1848 Jan 71


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