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

Cisplatin (cis-diamminedichloroplatinum II) has emerged as an anticancer drug of considerable value for the chemotherapy of several human neoplasms. However, this agent often causes renal toxicity, which appears to be the dose-limiting untoward effect. The present animal study was undertaken to compare, with regard to kidney injury and renal tissue repair, cisplatin and carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II), a platinum derivative more recently introduced in clinics. Female Sprague-Dawley rats (four animals per group) were treated ip with cisplatin (4 or 8 mg/kg, delivered in four consecutive daily injections) or carboplatin (40 mg/kg given in one injection) and terminated 4, 7, and 21 days after drug administration. One hour prior to sacrifice, each animal received ip 200 microCi of [3H]thymidine for the measurement of DNA synthesis and cell proliferation (frequency of S-phase cells in renal tissue, determined by histoautoradiography). Cisplatin, particularly at 8 mg/kg, caused severe tubular injury (acute tubular necrosis) culminating in a long-lasting cystic tubular dilatation in the outer stripe of outer medulla. Tubular damage was followed by a sharp proliferative response, indicative of tubular regeneration. However, the proliferative activity was still above basal level at the end of the observation period, suggesting that the tissue repair process had not reached completeness 3 weeks after cisplatin administration. In contrast, carboplatin only induced focal tubular necrosis in proximal tubules. Distal and collecting tubules also showed ultrastructural evidence of hydropic degeneration after exposure to the latter drug. Renal tubular injury associated with carboplatin was followed by a mild proliferative response. From this study, we can infer that carboplatin is less nephrotoxic than cisplatin, but still causes histopathological alterations in renal tissue. Furthermore, the lesser nephrotoxicity of carboplatin has a primary origin and is not due to a more efficient tissue repair reaction.
Exp Mol Pathol 1989 Oct
PMID:Tissue injury and repair in the rat kidney after exposure to cisplatin or carboplatin. 268 May 78

Rats were injected intraperitoneally with HgCl2 at doses of 2.5, 5, 7.5, and 10 mumol of Hg/kg. Urine was collected over a 24-hr period. At this time, plasma samples were taken and kidney damage was assessed by histological examination. Urinary gamma-glutamyltransferase levels were significantly elevated at Hg2+ doses of 7.5 and 10 mumol/kg, consistent with the detection of acute tubular necrosis by light microscopy. Resonances for a large number of low molecular weight metabolites were assigned in high resolution 1H NMR spectra of rat urine. Spectra from small volumes of urine (about 0.5 ml) were obtained in less than 5 min with no pretreatment. Significant Hg2+ dose-related decreases in the excretion of creatinine and citrate and increases of glucose, glycine, alanine, alpha-ketoglutarate, succinate, and acetate were detected. Elevated levels of lactate and creatinine in plasma of rats receiving the two highest doses were found by 1H NMR. There was a good correspondence between the histopathology, enzyme excretion, and 1H NMR urinary metabolite fingerprints in the assessment of Hg2+-induced renal damage. 1H NMR provided a sensitive measure of mercury-induced nephrotoxic lesions, and information on the molecular basis of mercury cytotoxicity was derived from the abnormal patterns of metabolite excretion. These suggested that primary metabolic effects of mercury were upon mitochondrial metabolism, in particular inhibition of certain citric acid cycle enzymes leading to decreased utilization of alpha-ketoglutarate and succinate by the renal tubular cells. The decrease in urinary citrate associated with Hg2+ dosing was attributed to intracellular, tubular acidosis with concomitant enhanced citrate reabsorption. The acidosis was assumed to arise from a combination of the inhibition of tubular carbonic anhydrase and a mild metabolic lactic acidosis due to increased activity of anaerobic pathways in the kidney. The possible extension of the 1H NMR techniques to the investigation of the nephrotoxic potential of other compounds and drugs is discussed.
Mol Pharmacol 1985 Jun
PMID:Proton NMR spectra of urine as indicators of renal damage. Mercury-induced nephrotoxicity in rats. 286 May 59

A model of acute blood loss in rats with a reproducible mortality rate over a wide range of body weights was developed by withdrawing various amounts of fixed blood volume per 100 g body weight via the left common carotid artery and observing the survival of the animals. Younger (lighter) animals survived the bleeding longer than older (heavier) animals. As early as 70 min following the shock episode there was evidence of acute tubular necrosis in kidney proximal tubules and focal centrilobular necrosis in the liver. The 84%, 50%, or 16% body weight - mortality line was: V84 = -0.17 BW + 3.25; V50 = -0.18 BW + 3.16; or V16 = -0.18 BW + 3.01 in animals ranging from 250 to 400 g body weight (where V = bleeding volume ml/100 g body weight, BW = body weight in grams X 10(-2). To produce the same mortality rate, the bleeding volume per unit body weight decreased with increased body weight. On the other hand, the bleeding volume per total blood volume or per unit body surface area increased with increased body weight. The body weight-mortality line is a useful method to calculate the bleeding volume to produce predetermined mortality rate. This method can be easily applied to various pathophysiological and metabolic studies on the nature of acute blood loss as well as in the treatment of acute blood loss.
Virchows Arch B Cell Pathol Incl Mol Pathol 1985
PMID:Pathophysiology of hemorrhagic shock. A model for studying the effects of acute blood loss in the rat. 286 91

Studies were undertaken to determine the long-term effects of the nephrotoxin, uranyl nitrate, on the function and structure of the rat kidney. Animals were injected with 10 mg/kg B.Wt. of uranyl nitrate and renal function studies were performed one, two, four and eight weeks after drug administration. Light microscopy and scanning and transmission electron microscopy were used to characterize the morphologic changes at each time interval. Glomerular filtration rate was significantly reduced (P less than 0.01) one week (0.18 +/- 0.06 ml/min/100 gm B.Wt.) and two weeks (0.54 +/- 0.09 ml/min/100 gm B.Wt.) after drug treatment compared to controls (1.01 +/- 0.4 ml/min/100 gm B.Wt.) and returned to normal values by four weeks. The fractional excretion of sodium was significantly increased (P less than 0.01) one week after uranyl nitrate treatment (2.45% +/- 0.82) compared to controls (0.29% +/- 0.11). No further differences in this parameter were noted after one week. At all time intervals studied the pars recta of the proximal tubule (S2 and S3 segments) was the most consistently damaged region of the nephron. Acute tubular necrosis and tubular regeneration of these segments were evident one and two weeks after drug administration. Many of the tubules were widely dilated and lined by low-lying squamous epithelial cells. By four weeks some of these pars recta segments could be classified as microcysts and this type of lesion persisted as long as eight weeks after treatment. Regeneration of most injured proximal tubules was complete by eight weeks. Atrophic proximal tubules, marked interstitial fibrosis and a mononuclear cell infiltration, consistent with a chronic type of injury, were noted at the later time intervals. These results suggest that uranyl nitrate induces a persistent injury to the kidneys of rats causing lesions as long as eight weeks after injection.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982
PMID:The long-term effects of uranyl nitrate on the structure and function of the rat kidney. 619 Mar 5

The present study was undertaken to examine a possible effect of aprotinin, a 6.5-kDa polypeptide with an inhibitory effect on proteolysis, on aminoglycoside nephrotoxicity. Experimental animals (female Sprague-Dawley rats, 175-200 g body wt) were treated for 4 days with 40 mg/kg gentamicin given ip at 12-hr intervals. Aprotinin (40,000 kIU per animal) was infused i.v. over a period of 8 days, using subcutaneously implanted miniosmotic pumps. In protocol A, infusion pumps were placed 4 days before starting gentamicin treatment. In protocol B, pumps were implanted 15-18 hr prior to first gentamicin administration. In addition to rats exposed to both gentamicin and aprotinin (GAP), animals were treated with gentamicin ip+saline i.v. (G), saline ip+aprotinin i.v. (AP), or received only saline by both routes of administration (C). All rats were terminated 4 days after the end of gentamicin dosing. One hour before sacrifice, 200 microCi of [3H]thymidine was given ip to each animal in order to monitor cell turnover in renal tissue. The kidneys were analyzed with respect to (i) histopathological alterations and renal dysfunction, (ii) aminoglycoside tissue accumulation, and (iii) tubular regeneration (measurement of cell proliferation). In animals receiving aprotinin alone, histological examination of renal cortex on paraffin sections disclosed mild tubular injury with focal cell necrosis. In plastic-embedded tissue, proximal tubule epithelium was characterized by the presence of numerous inclusions densely stained with toluidine blue. At the ultrastructural level, these inclusions appeared filled with amorphous electron-dense material. In gentamicin-treated animals, cortical drug accumulation reached values higher than 0.3 mg/g renal tissue, but a significant 30-40% decrease of gentamicin accumulation was noted in GAP groups, compared to G groups. Histological examination of renal cortex (paraffin sections) revealed the development of acute tubular necrosis in both G and GAP groups. Tubular injury was accompanied by mild renal dysfunction, as shown by the level of serum creatinine which was increased almost 3-fold in the G group, compared to C and AP groups. Aprotinin infusion produced a further increase of serum creatinine, particularly in protocol A where it was 72% higher for the GAP group than for the G group. In both G and GAP groups, postnecrotic tubular regeneration was evidenced by determining the rate of DNA synthesis and the frequency of S-phase cells in renal cortex. Both methods gave consistent results and showed a 8- to 13-fold increase of cell proliferation in groups receiving gentamicin alone, compared to C groups.(ABSTRACT TRUNCATED AT 400 WORDS)
Exp Mol Pathol 1994 Jun
PMID:Potentiation of gentamicin nephrotoxicity in the rat by infusion of aprotinin. 752 40

To elucidate the role of apoptosis and cell desquamation in the repair phase of acute tubular necrosis, morphological findings after 60 min ischaemia were investigated in rats. A morphometric analysis of the cell proliferation and of the epithelial cellularity of reconstructing tubules was performed. The kinetics of apoptosis and cell desquamation were also examined. Ischaemia and reperfusion injury resulted in widespread necrosis of tubules at day 1. Subsequently, a regenerative epithelial hyperplasia took place in the early stage. The most marked increase in cellularity in the damaged tubules was on day 6, when the tubules became lined by hyperplastic epithelial cells with papillary clusters. The number of papillary clusters decrease up to day 8, and during this period many desquamated cells from the clusters were observed in the tubular lumen. In the later stage, hyperplastic epithelial cells were reduced to their original cellularity and during this period the number of apoptotic cells obviously increased, while the damaged tubules were reconstructed. We conclude that epithelial overproduction occurs in the early phase after tubular necrosis, and excess hyperplastic epithelial cells regress during the repair process by cell desquamation and apoptosis, both of which are essential for the recovery of the original tubular structure.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Apoptosis and cell desquamation in repair process of ischemic tubular necrosis. 824 76

Despite advances in medical technology, acute renal failure (ARF) still represents a major challenge in clinical medicine, as morbidity and mortality have remained unchanged over the past two decades. The pathophysiology of ARF is highly complex and only poorly understood; new insights into the pathophysiology of ARF are therefore of utmost importance to develop better understanding and therapies. Acute tubular necrosis (ATN) is the predominant cause of ARF and often arises as a consequence of septic, toxic, or ischemic insults. The recruitment of leukocytes into the kidney has recently emerged as a key event in the development of experimental ischemic and septic ARF. A few descriptive clinical studies support this idea. However, the clinical relevance of various animal models remains unclear, as does the importance of different leukocyte subsets, and even methodological aspects as how to quantify renal leukocyte recruitment. This review summarizes and critically evaluates experimental findings that provide insight into the role of leukocytes and their recruitment during ARF. We aim to provide a valid description of ARF, illustrate animal models of ARF, review qualitative and quantitative methods to assess renal leukocyte recruitment, and discuss the components of the leukocyte recruitment cascade and their role in ARF.
J Mol Med (Berl) 2004 Feb
PMID:Leukocyte recruitment and acute renal failure. 1466 1

Acute tubular necrosis (ATN) ranges from minimal histologic changes to overt necrotic tubules. Although histologic changes on routine stained sections can be seen in many ATN cases, they may be subtle in some cases. In some cases, electron microscopy may reveal more reliable findings to support a diagnosis of ATN. Thus, a molecular marker to confirm acute tubular damage and to differentiate mild from moderate tubular injury could provide more reliable detection of ATN at the light microscopic level. In this study, sections from native and transplant renal biopsies with the diagnosis of ATN were stained immunohistochemically for p53, an upstream marker for DNA damage, and compared with donor baseline biopsies as controls. The transplant and native ATN kidney groups had significantly higher numbers of p53 nuclear staining in renal tubular epithelium (transplant ATN: 4.58 +/- 1.51/mm2, n = 18, and native ATN: 6.12 +/- 1.99/mm2, n = 13) than the donor baseline group (1.09 +/- 0.51/mm2, n = 16) or controls-normal renal parenchyma away from tumors (0.029 +/- 0.017). Cases with moderate ATN changes showed significantly increased p53 tubular staining (transplant ATN: 9.20 +/- 2.59/mm2, n = 8, and native ATN: 14.3 +/- 1.88/mm2, n = 5) when compared with the mild ATN cases (transplant ATN: 0.87 +/- 0.30/mm2, n = 10, and native ATN: 1.01 +/- 0.39/mm2; n = 8). In summary, there was direct correlation between nuclear p53 staining and morphologic changes seen microscopically and ultrastructurally, suggesting that p53 can be used as a reliable marker of cellular damage to aid in the diagnosis of ATN.
Appl Immunohistochem Mol Morphol 2004 Sep
PMID:P53 protein is a reliable marker in identification of renal tubular injury. 1555 35

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.
Mol Cell Biochem 2007 Oct
PMID:Favorable balance of anti-oxidant/pro-oxidant systems and ablated oxidative stress in Brown Norway rats in renal ischemia-reperfusion injury. 1745 15

Ischaemia followed by reperfusion (I/R) can induce inflammation and injury and is a risk factor for delayed graft function and rejection of transplanted kidneys. Inflammation is regulated by NF-kappaB transcription factors which induce pro-inflammatory molecules in endothelial cells (EC). We examined whether A20, a negative regulator of NF-kappaB, can protect kidneys from I/R injury. To mimic the fluctuations in endothelial oxygenation that occur during I/R we exposed cultured human umbilical vein EC (HUVEC) to hypoxia (1% O(2) for 4 h) followed by re-oxygenation (21% O(2) for 1 h-24 h). We observed transient expression of pro-inflammatory molecules (E-selectin, VCAM-1 and IL-8) and sustained expression of A20 in HUVEC exposed to hypoxia/re-oxygenation. The effect of A20 on endothelial responses to hypoxia/re-oxygenation was assessed. We observed that pre-treatment of HUVEC with an adenovirus containing A20 (Ad-A20) suppressed activation of NF-kappaB and induction of pro-inflammatory molecules by hypoxia/re-oxygenation, whereas a control adenovirus had little or no effect. Thus the induction of A20 may form a negative feedback loop in pro-inflammatory signalling in cells exposed to hypoxia/re-oxygenation. To validate our cell culture experiments we examined the role of A20 in renal responses to I/R. We observed that A20 was induced in rat kidneys exposed to I/R. Moreover, pre-treatment of animals with Ad-A20 significantly reduced acute tubular necrosis, renal expression of VCAM-1 and NF-kappaB activation in response to I/R, whereas pre-treatment with control adenovirus did not. Our observations suggest that A20 maintains physiological homeostasis in kidneys exposed to I/R by protecting them from inflammation and injury.
J Mol Med (Berl) 2008 Dec
PMID:The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation. 1894 30


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