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)

Interleukin-1 (IL-1) is a central component of many acute inflammatory processes. Blocking IL-1 receptor (IL-1R) with IL-1R antagonist (IL-1Ra) has attenuated ischemic reperfusion injury in brain, heart, and liver models. However, the role of IL-1 in renal ischemic reperfusion injury (IRI) is not known. Therefore, the role of IL-1 in renal IRI was evaluated using the complementary approaches of IL-1R blockade in wild-type mice in addition to the study of renal IRI in IL-1R knockout (KO) mice. Ischemia was induced by bilateral renal pedicle clamping for 30 min. IL-1Ra was administered at 10 mg/kg every 4 h, high doses that have been protective in previous organ injury models in mice. IL-1R KO animals, previously characterized as insensitive to IL-1, had the absence of IL-1R1 confirmed by DNA blots. IL-1Ra, IL-1R KO, and control groups had similar elevations of blood urea nitrogen (114 +/- 13, 133 +/- 11, and 120 +/- 11 mg/dl) and serum creatinine (1.7 +/- 0.3, 2.1 +/- 0.2, and 1.6 +/- 0.3 mg/dl) 24 h after ischemia. Furthermore, acute tubular necrosis scores were also similar in IL-1Ra-treated mice (3.0 +/- 0.3), IL-1R KO mice (2.7 +/- 0.3), and control mice (3.1 +/- 0.2). However, both IL-1Ra and IL-1R KO groups, compared with control animals, developed significantly less infiltration of polymorphonuclear leukocytes per 10 high-power fields in postischemic renal tissue (1111 +/- 228 and 967 +/- 198 versus 1820 +/- 190, P < 0.05). In contrast to the comparable renal functions at 24 h, recovery of renal function was significantly accelerated in the IL-1R KO group compared with control at both 48 (P < 0.05) and 72 (P < 0.05) h. Recovery in the IL-1Ra group was similar to that in the control animals. These data demonstrate that IL-1 is unlikely to be beneficial in the recovery of renal function after ischemia and may play a deleterious role.
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PMID:Role of IL-1 in renal ischemic reperfusion injury. 955 64

There are two fundamentally different growth responses for cells comprising the nephron: hyperplasia or hypertrophy. Cells that progress through the normal cell cycle double their DNA content and eventually divide during mitosis. Those cells that hypertrophy stop the growth process in the G1-phase of the cell cycle; while they increase in size, protein and RNA content, they cannot duplicate their set of chromosomes because they never pass through the S-phase of the cell cycle. Hypertrophy may be an early compensatory mechanism to initially replace the loss of functioning tissue, however, this maladaptive process eventually fosters progressive loss of renal function. Since progression of the cell through the G1 to S-phases is regulated by cyclins D, E and A, which in turn bind and activate cyclin dependent kinases (CDKs), evidence has been accumulating on a particular CDK-inhibitor protein, p27Kip1, which is speculated to be a key to the complex process of the G1/S cell cycle transition. This article examines the mechanisms of the proliferative growth response following acute tubular necrosis, and compensatory hypertrophy of glomerular and tubule cells, with a particular focus on the protein p27Kip1.
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PMID:Molecular mechanisms of renal hypertrophy: role of p27Kip1. 1050 70

Prothrombin has remarkable affinity for calcium oxalate crystals. It is produced in renal tubular cells and is detected as a urinary form of prothrombin F1. The aim of this basic study was (1) to isolate prothrombin mRNA from normal human and rat kidneys; (2) to confirm expression level changes in stone-forming rat kidneys; and (3) to analyze the DNA sequence of renal prothrombin. The aim of the clinical investigation was to measure the serum levels of renal prothrombin in clinical cases of various urologic diseases. The expression of prothrombin mRNA in human kidneys and male Wistar rat kidneys was investigated using reverse transcription-PCR, with prothrombin (F1, F2, and thrombin) primers. Renal prothrombin levels were measured in the sera of patients with renal cell carcinoma, renal transplant donors, patients with chronic renal failure, and renal transplant recipients, using an enzyme-linked immunosorbent assay. Expression of cyclophilin as well as prothrombin mRNA could be detected. Prothrombin mRNA expression levels seemed to be increased in stone-forming rats. The DNA sequence of renal prothrombin differed from that of liver prothrombin at three points. Repeated measurements of renal prothrombin showed that values were high during the acute tubular necrosis period and tended to decrease with the recovery of renal function. Prothrombin mRNA expression could be confirmed in human and rat kidneys, as well as in stone-forming rat kidneys. Serum concentration measurements can be considered useful for assessment of recovery from acute tubular necrosis after renal transplantation and for diagnosis of acute rejection.
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PMID:Gene expression of prothrombin in human and rat kidneys: basic and clinical approach. 1054 Dec 74

Focal tubular cell multiplication at sites on an injured nephron is a critical event in the recovery phase following acute tubular necrosis. During this process, numerous viable tubular cells exfoliate and are shed into the urine. Lysophosphatidic acid (LPA) is generated in the plasma membrane of injured cells and acts as an intercellular mediator of various biological processes, including inflammation, proliferation and repair. In the present study, exfoliated proximal tubule (PT) cells were isolated from human urine and the mitogenic effects of LPA were investigated as a model of repair and proliferation following renal injury. LPA stimulated a 23. 5% increase in DNA synthesis, a 29.4% increase in cell number and an 86.6% decrease in cAMP content. All of these responses were pertussis toxin sensitive, indicating the involvement of G(i)-type G-proteins in LPA signalling. Conversely, the LPA-induced DNA synthesis and the decrease in intracellular cAMP content were insensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), suggesting a mitogenic response via PI3K-independent mechanisms. Furthermore, we detected specific mRNA transcripts for the recently cloned human LPA-receptors, endothelial differentiation gene (Edg)-2 and Edg-4 (Edg-2>>Edg-4) by reverse transcription-PCR in PT cells. Our data suggest that LPA may behave as a local growth factor in PT cells following tubular injury.
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PMID:Mitogenic action of lysophosphatidic acid in proximal tubular epithelial cells obtained from voided human urine. 1109 1

In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value
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PMID:Hepatocyte growth factor receptor in acute tubular necrosis. 1118 1

This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors.
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PMID:Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. 1209 87

Hepatocyte growth factor (HGF) enhances proliferation of renal epithelial cells as well as hepatocytes. HGF accelerates recovery from acute renal failure (ARF) in animal models. However, pharmacological profiles of HGF including its action mechanism has not been studied in detail. An HgCl(2)-induced ARF mouse was used in this study to evaluate the efficacy of HGF. Single administrations of recombinant human HGF or vehicle were given to ARF mice 30 min after HgCl(2) injection. Renal function was monitored by measuring serum creatinine, blood urea nitrogen and creatinine clearance. In the ARF mice, there was a deterioration of renal function biochemical parameters and histological evidence of renal damage including acute tubular necrosis of proximal tubules. These were both significantly ameliorated by a single HGF administration. The effect of HGF was noticeable in the early phase of ARF (1 day after onset) when there was no histological evidence of increased labeling indexes in renal tubular epithelial cells. Western blot analysis of the c-Met/HGF receptor showed that tyrosine phosphorylation was enhanced immediately after HGF administration indicating direct activation of renal epithelial cells. HGF prevented increase of apoptotic nuclei with DNA fragmentation in renal epithelial cells which suggests cytoprotective activity of HGF on renal epithelial cells in the ARF mice.
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PMID:Hepatocyte growth factor protects functional and histological disorders of HgCl(2)-induced acute renal failure mice. 1181 5

Kidney injury is repaired by inflammatory and non-inflammatory mechanisms, with the extent of recovery based on severity of the insult. Critical to the assessment of kidney repair is the ability to differentiate functional recovery from structural repair: compensatory increases in the function of intact residual nephrons often mask the inability of the kidney to heal or replace damaged structures. The mechanisms of repair reflect three levels of injury, which are handled differently by the kidney. First, DNA damage is countered by proof-reading DNA polymerases, backed by other controls for sequence misalignment/nucleotide replacement. If DNA cannot be repaired, cells harboring mutation(s) are lost through apoptosis, which is also critical to the disposal of kidney cells and infiltrating leukocytes in both acute and chronic ischemic, immunological, or chemical damage. This leaves room for a second mechanism of repair, i.e., cellular proliferation. At least 5 types of reparative proliferation are known to occur, some of which involve stem cell differentiation and perhaps immigration from distant reservoirs. The final type of repair is referred to as structural repair, actually quite limited by lack of postnatal nephrogenesis in the human kidney. Certain forms of recovery after acute tubular necrosis involve extensive remodeling of the proximal tubule, where integrity of the basement membrane is required for successful repair. Contrary to the long-held belief that only acute injury can be repaired, while ongoing chronic damage leads to progressive nephron loss, evidence is emerging that some degree of renal remodeling occurs even in the presence of persistent structural changes.
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PMID:Mechanisms of repair after kidney injury. 1276 65

Recovery from kidney injury through repair mechanisms often linked to inflammation is conditioned by nature and severity of the insult. In the assessment of kidney repair, functional recovery should be kept distinct from structural repair: compensatory hypertrophy/function of intact nephrons often masks the inability of the kidney to heal or replace damaged structures. The mechanisms of repair reflect three degrees of injury, differently handled by the kidney. First, repair of DNA damage is accomplished through proofreading DNA polymerases, along with other controls for sequence misalignment / nucleotide replacement. If DNA cannot be repaired, cells carrying mutation(s) are disposed of through apoptosis, which is also critical to clearing damaged kidney cells and infiltrating leukocytes in acute and chronic ischemic, immunological, or chemical damage. A second mechanism of repair is linked to proliferation of surviving cells. At least 5 types of reparative proliferation are known to occur, some of which implicate stem cell immigration from distant reservoirs, followed by in situ differentiation. A third mode of repair could be referred to as structural repair, indeed limited in the human kidney by the absence of postnatal nephrogenesis. Recovery from acute tubular necrosis involves remodelling of the proximal tubule, with a strict requirement for integrity of the basement membrane. Contrary to the current dogma that only acute injury can be repaired, whereas chronic damage leads to irreversible loss of nephrons, evidence is emerging that some degree of renal remodelling occurs even in chronic renal disease, despite the occurrence of stabilized structural changes.
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PMID:[Mechanisms of repair after renal injury]. 1288 44

Fatty acids constitute a major source of metabolic fuel for energy production in kidney tissue. During acute renal failure (ARF) injury to the proximal tubule and medullary thick ascending limb leads to structural and functional alterations that result in reduced expression and activity of mitochondrial and peroxisomal fatty acid oxidation (FAO) enzymes. Reduced DNA binding activity of peroxisome proliferator activated receptor-alpha (PPARalpha) to its target genes and decreased expression of its tissue-specific coactivator PPAR-gamma-coactivator-1 (PGC-1) in the mouse proximal tubule and the medullary thick ascending limb, represent 2 potential mechanisms that account for the observed alterations of FAO during ARF. Pretreatment with PPARalpha ligands restores the expression and activity of renal FAO enzymes, and this metabolic alteration leads to amelioration of acute tubular necrosis caused by ischemia/reperfusion or cisplatin-induced ARF. More studies are needed to examine further the cellular mechanisms of substrate inhibition, and to determine if metabolic pathways, in addition to the recovery of FAO, account for the protective effect (s) of PPARalpha ligands during acute renal failure.
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PMID:Energy metabolism and cytotoxicity. 1368 May 32


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