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Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To examine the mechanisms involved in the progression of mercury chloride (HgCl2)-induced acute tubular necrosis (ATN), we investigated the histopathological changes and the expression of inducible nitric oxide synthase (iNOS) mRNA and protein in renal cortices of rats at 20 hours after exposure to HgCl2. The expression of iNOS mRNA was significantly augmented in renal cortices of rats with HgCl2-induced acute renal failure (ARF). Likewise, the induction of iNOS protein was observed in damaged proximal tubule epithelial cells of rats with HgCl2-induced ARF. Pretreatment of rats with iNOS inhibitor aminoguanidine, however, suppressed the development of proximal tubule epithelial cell injury and prevented an increase in blood urea nitrogen and serum creatinine as well as resulting in a marked fall in iNOS mRNA and protein in rats with HgCl2-induced ARF. These observations indicate that the induction of iNOS may play a role in the progression of HgCl2-induced ATN through the exacerbation of proximal tubule epithelial cell damage.
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PMID:Inducible nitric oxide synthase expression in mercury chloride-induced acute tubular necrosis. 981 Jan 45

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

It was reported that reactive oxygen metabolites play an important role in the pathogenesis of several renal diseases including glomerulonephritis, ischemia and acute tubular necrosis. However, the effect of oxidants and protective effect of sex steroid hormones on Na+/glucose cotransporter of renal proximal tubular cells is not yet elucidated. In the present study, we examined the effect of sex steroid hormones against tert-butyl hydroperoxide (t-BHP)-induced alteration of Na+/glucose cotransporter activity in primary cultured rabbit renal proximal tubule cells (PTCs). t-BHP inhibited alpha-methyl-D-glucopyranoside (alpha-MG) uptake in a dose-dependent manner. t-BHP-induced inhibition of alpha-MG uptake was due not to Km but to the decrease of Vmax. 0.5 mM t-BHP-induced inhibition of alpha-MG uptake was significantly blocked by estradiol-17beta, but not by progesterone and testosterone. This protective effect was not blocked by estrogen receptor antagonist or transcription and translation inhibitor. In addition, 0.5 mM t-BHP increased [3H]-arachidonic acid (AA) release and Ca2+ uptake. These effects of t-BHP were also significantly blocked by estradiol-17beta, but not by progesterone and testosterone. Protective efficacy of estradiol-17beta on t-BHP-induced inhibition of alpha-MG uptake is exhibited between antioxidants and iron chelators. In conclusion, estradiol-17beta, but not progesterone and testosterone, partially prevented t-BHP-induced inhibition of alpha-MG uptake through its antioxidant activity dependent upon phenol structures and inhibition of AA release and Ca2+ influx.
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PMID:Effects of sex hormones on Na+/glucose cotransporter of renal proximal tubular cells following oxidant injury. 1152 8

The straight segment (S3) of the proximal tubule is predominantly damaged during renal ischemia-reflow, whereas medullary thick ascending limbs (mTALs) are principally affected in other models of hypoxic acute tubular necrosis (ATN). Since the latter injury pattern largely depends on the extent of reabsorptive activity during hypoxic stress, we hypothesized that proximal tubular damage might attenuate downstream mTAL injury by means of diminished distal solute delivery for reabsorption. In isolated rat kidneys perfused for 90 min with oxygenated Krebs-Henseleit solution, mTAL necrosis developed in 75 +/- 3% of tubules in the mid-inner stripe of the outer medulla. By contrast, S3 segments in the outer stripe were minimally affected, with tubular fragmentation involving some 5 +/- 2% of tubules. In kidneys subjected in vivo to proximal tubular injury and subsequently used for isolated perfusion studies, the injury pattern was inverted: following 20 and 30 min ischemia and reflow for 24 h, S3 fragmentation rose to 18 +/- 16% and 72 +/- 13%, while mTAL damage was reduced to 33 +/- 10 and 24 +/- 8%, respectively. In kidneys subjected in vivo to D-serine S3 necrosis rose to 100%, while mTAL damage fell to 1 +/- 1% (p < 0.001). Substantial S3 tubular collapse (involving approximately 30% of tubules) and inner stripe interstitial hemorrhage were also noted, exclusively in kidneys subjected to ischemia-reflow. Proximal tubular necrosis alone or in combination with collapse inversely correlated with mTAL necrosis (R = -0.51 and -0.72, respectively, p < 0.003). This cogent inverse association might imply that disruption of the proximal nephron attenuates downstream mTAL necrosis by a reduction of distal tubular reabsorptive workload.
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PMID:Proximal tubular injury attenuates outer medullary hypoxic damage: studies in perfused rat kidneys. 1209 29

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

Previous studies demonstrated that during cisplatin-induced acute renal failure, there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the effects of peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligand Wy-14643 (WY) on the abnormalities of medium chain fatty acid oxidation and pyruvate dehydrogenase complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPAR alpha ligand WY ameliorated cisplatin-induced acute renal failure and prevented cisplatin-induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin-treated PPAR alpha null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPAR alpha agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPAR alpha ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPAR alpha agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPAR alpha ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
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PMID:PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity. 1461 80

Cisplatin injury to the kidney is characterized, in part, by inhibition of substrate oxidation, inflammation, and tubular cell death in the form of apoptosis and necrosis. Recently, we demonstrated that cisplatin-induced inhibition of substrate oxidation can be reversed by the administration of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands, resulting in amelioration of renal function. We therefore hypothesize that by improving fatty acid oxidation in vivo might protect renal function by reducing both apoptosis and necrosis in cisplatin-treated mice. Mice subjected to a single intraperitoneal injection of cisplatin developed acute renal failure (ARF) at days 3 and 4. At day 4 after cisplatin injection mRNA, protein levels and enzyme activity of proapoptotic renal endonuclease G (Endo G) were increased compared with saline-treated mice. In situ hybridization and immunohistochemical studies localized the increased expression of Endo G mRNA to the cytosolic compartment and Endo G protein to the nuclear compartment of proximal tubules in cisplatin-treated mice. Pretreatment of PPAR-alpha wild-type mice with PPAR-alpha ligand WY-14643 reduced significantly cisplatin-induced increased protein expression and enzyme activity of Endo G and prevented the nuclear translocation of mitochondrial Endo G. Morphological examination of tubular injury in the PPAR-alpha wild-type mice that received PPAR-alpha ligand and cisplatin did show significant amelioration of acute tubular necrosis, as well as a significant reduction in the number of apoptotic cells in the proximal tubule when compared with the cisplatin-treated group. In contrast, in PPAR-alpha-null mice treated with the ligand and cisplatin, Endo G protein expression was not reduced and this was accompanied by lack of protection of kidney function. We conclude that PPAR-alpha ligand protects against cisplatin-induced renal injury via a PPAR-alpha-dependent mechanism by reducing the expression and enzyme activity of proximal tubule Endo G, which results in amelioration of both proximal tubule cell apoptosis and necrosis.
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PMID:PPAR-alpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G. 1528 Jan 56

Paraquat (PQ) toxicity produces severe injures in many major organs systems, including kidney, developing renal failure with fatal evolution in most of the cases. Several antidotes have been used in the treatment of paraquat intoxication without satisfactory results. The antioxidative effect of melatonin (MLT) and sodium thiosulphate (STS) on kidney in rats with acute intoxication by PQ was studied. Forty male Wistar rats were used, divided in 4 groups of 10 rats each. Group I, control, was injected intraperitoneally (ip) with 1 ml of saline solution; group II, received DL50 of PQ, ip; groups III and IV, DL50 of PQ, and simultaneously the first dose of MLT (15 mg/kg, ip) or STS (1,5 g/kg, i.p.) respectively. Thirty minutes later, groups III and IV received a second similar dose of MLT and TSS. After 24 hours, rats were sacrificed with pentobarbital, and kidneys were extracted for morphological study. Light and electronic microscopy observations showed in group II morphological changes of acute tubular necrosis in proximal tubule in group II, similar findings, with lesser magnitude, were observed in the animals treated with the antidotes, suggesting a partial protection. In conclusion, individual use of MLT and STS at the doses and time used partially prevent damage caused by paraquat to the cell. In consequence, more experiments with these drugs are necessary to considere them as specific treatments in cases of poisoning by paraquat.
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PMID:[Protective effect of melatonin and sodium thiosulphate on histopathology and ultrastructure of the kidney in rats with acute paraquat poisoning]. 1743 46


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