Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal ischaemia-reperfusion (I/R) injury is a clinically significant problem and an invariable consequence of renal transplantation. The problem begins at the onset of acute tubular necrosis (ATN), when the transplantation takes a long ischaemic interval by using the cardiac arrest donor's kidney. In addition, the longer the ischaemic interval, the higher the incidence rate of ATN. It is clinically important that renal I/R injury is reduced. The antisense oligodeoxynucleotide (AS-ODN), developed as a therapy for intractable diseases at the gene level, has recently been established as an important method in examining specific gene functions. The authors have previously demonstrated that AS-ODN/tissue factor (TF) prevents renal I/R injury. This review discusses the efficacy of AS-ODN/TF and AS-ODN/intercellular adhesion molecule-1 as existing targets, and the potential of AS-ODN/nuclear factor-kappaB, AS-ODN/cyclooxygenase and AS-ODN/5-lipoxygenase as prospective targets.
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PMID:Prospects of antisense oligodeoxynucleotides to alleviate renal ischaemia-reperfusion injury. 1557 55

Acute renal failure (ARF) is an abrupt decline of renal function, and acute tubular necrosis (ATN) is its more frequent expression. Recent contributions in physiopathological knowledge, specially in post-ischemic ARF, are scarcelly reflected in therapy. Morbidity and mortality due to ARF are very high, mainly in critically ill patients. Prevention and treatment of ATN are based in avoiding nephrotoxicity and renal ischemia. An adequate evaluation of renal risk factors in hospitalized patients is important. Maintaining euvolemia, effective cardiac output and adequate renal perfussion pressure are three paramount factors in ischemia prevention. The best dialytic schedule is not universally accepted. ARF replacement therapy must be flexible, tailoring techniques (IHD, SLED, CRRT) to the clinical situation of patients. There is not a consensus in dialysis dose in ARF. Nevertheless, despite a robust scientific evidence is lacking, some data suggest that a delivered minimum dose of sKtV >1 in IHD or >35 ml/kg/h in CRRT would be beneficial for patient survival.
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PMID:[Common places on clinical management of acute renal failure]. 1605 Mar 94

Chemokines play a major role in the recruitment of leukocytes in inflammation and in the regulation of T helper 1 (Th1)/Th2 immune responses. These mechanisms have been recognized to be important in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The interaction of the CXC chemokine receptor 3 (CXCR3) receptor with its ligands is a key pathogenic pathway in promoting inflammation and in enhancing Th1 immune responses. After the induction of ischemia in the mouse model of renal ischemia, an increase in intrarenal expression of CXCR3 and its ligands was observed. Compared with the wild-type (WT) mice, CXCR3-deficient mice (CXCR3-/-) had significantly lower serum creatinine levels, better survival rate, and significantly less acute tubular necrosis and cellular infiltrates. In the kidney, intracellular staining of infiltrating cells that were recovered from kidneys revealed a lower percentage of CD4+IFN-gamma+ cells in the CXCR3-/- mice compared with the WT mice. Furthermore, adoptive transfer of WT CD3+ cells into CXCR3-/- mice before induction of I/R injury abrogated the protection of CXCR3-/- mice from I/R injury. It is concluded that CXCR3 plays an important role in orchestrating the recruitment of Th1 cells to the ischemic kidney and in mediating I/R injury and therefore may serve as a novel target for the therapy of I/R injury.
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PMID:Role of CXC chemokine receptor 3 pathway in renal ischemic injury. 1648 10

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

Oxidative stress is important in the pathogenesis of renal ischemia-reperfusion (IR) injury; however whether imbalances in reactive oxygen production and disposal account for susceptibility to injury is unclear. The purpose of this study was to compare necrosis, apoptosis, and oxidative stress in IR-resistant Brown Norway rats vs. IR-susceptible Sprague-Dawley (SD) rats in an in vivo model of renal IR injury. As superoxide (O (2) (.-) ) interacts with nitric oxide (NO) to form peroxynitrite, inducible NO synthase (iNOS) and nitrotyrosine were also examined. Renal IR was induced in SD and BN rats by bilateral clamping of renal arteries for 45 min followed by reperfusion for 24 h (SD 24 and BN 24, respectively). BN rats were resistant to renal IR injury as evidenced by lower plasma creatinine and decreased acute tubular necrosis. TUNEL staining analysis demonstrated significantly decreased apoptosis in the BN rats vs. SD rats after IR. Following IR, O (2) (.-) levels were also significantly lower in renal tissue of BN rats vs. SD rats (P < 0.05) in conjunction with a preservation of the O (2) (.-) dismutating protein, CuZn superoxide dismutase (CuZn SOD) (P < 0.05). This was accompanied by an overall decrease in 4-hydroxynonenal adducts in the BN but not SD rats after IR. BN rats also displayed lower iNOS expression (P < 0.05) resulting in lower tissue NO levels and decreased nitrotyrosine formation (P < 0.01) following IR. Collectively these results show that the resistance of the BN rat to renal IR injury is associated with a favorable balance of oxidant production vs. oxidant removal.
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PMID:Favorable balance of anti-oxidant/pro-oxidant systems and ablated oxidative stress in Brown Norway rats in renal ischemia-reperfusion injury. 1745 15

Ischemia-reperfusion injury is a common early event in kidney transplantation and contributes to a delay in organ function. Acute tubular necrosis, impaired kidney function and organ leukocyte infiltration are the major findings. The therapeutic potential of stem cells has been the focus of recent research as these cells possess capabilities such as self-renewal, multipotent differentiation and aid in regeneration after organ injury. FTY720 is a new synthetic compound that has been associated with preferential migration of blood lymphocytes to peripheral lymph nodes instead of inflammatory sites. Bone marrow stem cells (BMSC) and/or FTY720 were used as therapy to promote recovery of tubule cells and avoid inflammation at the renal site, respectively. Mice were submitted to renal ischemia-reperfusion injury and were either treated with two doses of FTY720, 10x10(6) BMSC, or both in order to compare the therapeutic effect with non-treated and control animals. Renal function and structure were investigated as were cell numbers in peripheral blood and spleen. Activation and apoptosis markers were also evaluated in splenocytes using flow cytometry. We found that the combined therapy (FTY720+BMSC) was associated with more significant changes in renal function and structure after ischemia-reperfusion injury when compared with the other groups. Also a decrease at cell numbers and prevention of spleen cells activation and apoptosis was observed. In conclusion, in our model it was not possible to demonstrate the potential of stem cells alone or in combination with FTY720 to promote early kidney recovery after ischemia-reperfusion injury.
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PMID:Evaluation of stem cell administration in a model of kidney ischemia-reperfusion injury. 1799 70

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.
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PMID:Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review. 1803 25

Renal injury is known to trigger upregulation of many intracellular signal proteins, but those most sensitive in responding to renal injury remain debatable. We used gene microarray analysis to compare gene expression in rat kidneys subjected to early ischemia-reperfusion injury (30 min of renal ischemia and 3 hr of reperfusion) with non-ischemic kidneys as controls. Among 31,100 genes analyzed, microarray analysis revealed 21 genes with >3-fold increase in expression in ischemic kidneys compared to control non-ischemic kidneys. These upregulated genes included heat shock protein 70 (43-fold), heat shock protein 27 (12-fold), heme oxygenase-1 (10-fold), kidney injury molecule-1 (8-fold), and several subtypes of S100 calcium-binding proteins (3.1- to 7.5-fold). Following a prolonged reperfusion period (48 hr) after 30 min of ischemia, acute tubular necrosis was obvious in the S3 segment of proximal tubules of ischemic kidneys. Injured proximal tubules showed upregulated expression of heat shock protein 70 by immunohistochemistry and by Western blotting. These data suggest that heat shock proteins (eg, heat shock protein 70, heat shock protein 27, and heme oxygenase-1) are crucial for renal cell response to ischemic injury and that heat shock protein 70 is a highly sensitive intracellular marker of ischemia-reperfusion injury.
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PMID:Heat shock protein expression is highly sensitive to ischemia-reperfusion injury in rat kidneys. 1831 83

Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology. Although hemodynamic factors might play a role in the loss of glomerular filtration rate, they may not act through the induction of renal ischemia. Septic acute renal failure may, at least in patients with a hyperdynamic circulation, represent a unique form of acute renal failure: hyperemic acute renal failure. Measurements of renal blood flow in septic humans are now needed to resolve this pivotal pathophysiological question. Whatever may happen to renal blood flow during septic acute kidney injury in humans, the evidence available suggests that urinalysis fails to provide useful diagnostic or prognostic information in this setting. In addition, nonhemodynamic mechanisms of cell injury are likely to be at work. These mechanisms are likely due to a combination of immunologic, toxic, and inflammatory factors that may affect the microvasculature and the tubular cells. Among these mechanisms, apoptosis may turn out to be important. It is possible that, as evidence accumulates, the paradigms currently used to explain acute renal failure in sepsis will shift from ischemia and vasoconstriction to hyperemia and vasodilation and from acute tubular necrosis to acute tubular apoptosis or simply tubular cell dysfunction or exfoliation. If this were to happen, our therapeutic approaches would also be profoundly altered.
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PMID:Pathophysiology of septic acute kidney injury: what do we really know? 1838 94

Although renal tubular cell proliferation after acute tubular necrosis is an important and essential response in the recovery of renal dysfunction in acute renal failure, the precise factors and mechanisms of tubular cell regeneration remain unclear. Here, we describe our studies using a neutralizing antibody (Ab) against interferon-inducible protein of 10 kDa (IP-10; CXCL10) that indicate a role for CXCL10 in tubular cell proliferation after renal ischemia-reperfusion injury. Tissue necrosis and interstitial infiltrating numbers were comparable between anti-CXCL10 Ab-treated and control mice treated with IgG at the 24 and 48 h time points after reperfusion. In contrast, the numbers of Ki67-positive proliferating tubular cells were significantly increased in anti-CXCL10 Ab-treated mice 48 h after reperfusion. In accordance with the in vivo findings,in vitro studies using murine tubular epithelial cells indicated an antiproliferative effect of CXCL10 upon the intensity of cell proliferation and the number of Ki67-positive cells. These data suggest that CXCL10 plays a role in the regulation of tubular cell proliferation following renal ischemia-reperfusion injury.
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PMID:IFN-inducible protein 10 (CXCL10) regulates tubular cell proliferation in renal ischemia-reperfusion injury. 1852 Jan 67


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