Early effects of gentamicin, tobramycin, and amikacin on the human kidney

Broe, Marc E. De; Paulus, G.; Verpooten, Gert A.; Roels, Frank; Buyssens, N; Wedeen, Richard P.; Hoof, F. Van; Tulkens, Paul M.

doi:10.1038/ki.1984.69

Cited by 167 publications

(60 citation statements)

References 42 publications

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“…To investigate whether HB-EGF is produced in other types of acute renal injury, gentamicin-induced nephropathy was examined. Aminoglycoside is reported to be predominately a proximal tubule toxin, especially for S1 and S2 segments in cortex (45). Acute renal failure was induced by subcutaneous injection of gentamicin (400 mg/kg per d) and was evaluated by measurement of elevations of serum BUN and characteristic histopathological changes.…”

Section: Expression Of Hb-egf Mrna and Histological Localization Of Imentioning

confidence: 99%

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Sakai¹,

Zhang²,

Homma³

et al. 1997

J. Clin. Invest.

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We have recently reported that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA is induced in the rat kidney after acute ischemic injury. The present studies were designed to investigate whether bioactive HB-EGF protein is also produced in response to renal injury induced by either ischemia/reperfusion or aminoglycosides. Heparin-binding proteins were purified from kidney homogenates by heparin affinity column chromatography using elution with a 0.2-2.0 M gradient of NaCl. A single peak of proteins that eluted at 1.0-1.2 M NaCl was detected in the postischemic kidney within 6 h of injury. This eluate fraction stimulated DNA synthesis in quiescent Balb/c3T3, RIE, and NRK-52E cell lines, all of which are responsive to the epidermal growth factor family of mitogenic proteins. The EGF receptor of A431 cells was also tyrosine phosphorylated by this eluate peak. Furthermore, immunoblotting with a polyclonal antibody against rat HB-EGF indicated that the eluate peak contained immunoreactive proteins of 22 and 29 kD mol wt, consistent with the reported sizes of the secreted form and membrane anchored form of HB-EGF, respectively. Immunohistochemical studies revealed that HB-EGF was produced predominantly in distal tubules in kidneys injured either by ischemia/reperfusion or aminoglycoside administration. We also found that during metanephric development immunoreactive HB-EGF was detected in the ureteric bud as early as E14.5 and persisted in structures arising from the ureteric bud throughout embryogenesis. These results suggest that in response to acute injury, HB-EGF is produced predominantly in distal tubules and that endogenous HB-EGF may be an important growth factor involved in renal epithelial cell repair, proliferation, and regeneration in the early stages of recovery after acute renal injury, as well as in nephrogenesis.

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Section: Expression Of Hb-egf Mrna and Histological Localization Of Imentioning

confidence: 99%

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Sakai¹,

Zhang²,

Homma³

et al. 1997

J. Clin. Invest.

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“…Maneuvers that prevent gentamicin pinocytic uptake (59) and/or the development of lysosomal phospholipidosis (28) protect against nephrotoxicity. Together with the fact that the corresponding morphological and biochemical alterations develop early on in animals or humans treated with clinically relevant doses (10,32), this was the main argument that linked aminoglycoside cell toxicity to its lysosomal storage and the ensuing organelle dysfunction (40). Gentamicin, indeed, is a highly polar compound and is therefore largely considered to be unable to pass across membranes and to act outside of lysosomes.…”

mentioning

confidence: 99%

Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK ₁ Cells Subjected to Electroporation

Servais¹,

Jossin

Bambeke³

et al. 2006

Antimicrob Agents Chemother

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Gentamicin accumulates in the lysosomes of kidney proximal tubular cells and causes apoptosis at clinically relevant doses. Gentamicin-induced apoptosis can be reproduced with cultured renal cells, but only at high extracellular concentrations (1 to 3 mM; 0.4 to 1.2 g/liter) because of its low level of uptake. We recently showed that gentamicin-induced apoptosis in LLC-PK 1 cells involves a rapid (2-h) permeabilization of lysosomes and activation of the mitochondrial pathway of apoptosis (10 h). We now examine whether the delivery of gentamicin to the cytosol by electroporation would sensitize LLC-PK 1 cells to apoptosis. Cells were subjected to eight pulses (1 ms) at 800 V/cm (square waves) in the presence of gentamicin (3 M to 3 mM; 1.2 mg/liter to 1.2 g/liter); returned to gentamicin-free medium; and examined at 8 h for their Bax (a marker of mitochondrial pathway activation) contents by Western blotting and competitive reverse transcriptase PCR and at 24 h for apoptosis by 4,6-diamidino-2-phenylindole staining (confirmed by electron microscopy) and for necrosis (by determination of lactate dehydrogenase release). Nonelectroporated cells were incubated with gentamicin for 8 and 24 h. Significant increases in Bax levels (8 h) and apoptosis (24 h) were detected with 0.03 mM (13.2 mg/liter) gentamicin in electroporated cells compared with those achieved with 2 mM (928 mg/liter) in incubated cells. The increase in the Bax level was not associated with an increase in the level of its mRNA but was associated with the accumulation of ubiquitinated forms (probably as a result of impairment of its degradation by the proteasome). Assay of cell-associated gentamicin showed a marked, immediate, but transient accumulation in electroporated cells, whereas a slow, steady uptake was detected in incubated cells. The data indicate that cytosolic gentamicin triggers apoptosis. Sequestration of gentamicin in lysosomes would, to some extent, protect against apoptosis.

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“…In both cases, interactions of the drugs with membrane constituents have been suggested to play a major role in the onset of these toxic phenomena (36 -38). In addition, aminoglycosides are also taken up by proximal tubular cells of the renal cortex and accumulate in the lysosomes (39). This accumulation inhibits the activities of lysosomal phospholipases leading to phospholipidosis (40), which then triggers cell necrosis and renal failure (41).…”

Section: Discussionmentioning

confidence: 99%

Neamine Inhibits Xenografic Human Tumor Growth and Angiogenesis in Athymic Mice

Hirukawa

Olson

Tsuji

et al. 2005

Clinical Cancer Research

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Purpose: We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. Experimental Design: The effect of neamine on the nuclear translocation of angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. Results: Neamine effectively blocked the nuclear translocation of angiogenin in endothelial cells and inhibited angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. Conclusion: These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of angiogenin and may serve as an inhibitor for angiogenin-induced angiogenesis and cancer progression.

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Early effects of gentamicin, tobramycin, and amikacin on the human kidney

Cited by 167 publications

References 42 publications

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK ₁ Cells Subjected to Electroporation

Neamine Inhibits Xenografic Human Tumor Growth and Angiogenesis in Athymic Mice

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Early effects of gentamicin, tobramycin, and amikacin on the human kidney

Cited by 167 publications

References 42 publications

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK 1 Cells Subjected to Electroporation

Neamine Inhibits Xenografic Human Tumor Growth and Angiogenesis in Athymic Mice

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Gentamicin Causes Apoptosis at Low Concentrations in Renal LLC-PK ₁ Cells Subjected to Electroporation