Mechanism of aminoglycoside-induced lysosomal phospholipidosis: In vitro and in vivo studies with Gentamicin and Amikacin

Laurent, Guy; Carlier, Marie-Béatrice; Rollman, B.; Hoof, F. Van; Tulkens, Paul M.

doi:10.1016/0006-2952(82)90303-3

Cited by 225 publications

(125 citation statements)

References 33 publications

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“…On the cellular level an intense binding of the drug to the brush border of the proximal tubule could be demonstrated (Moestrup et al, 1995). After binding, gentamicin is taken into the cell by endocytosis where it inhibits the activities of lysosomal phospholipases and sphingomyelinase (Laurent et al, 1982). Therefore, gentamicin also inhibits the degradation of phospholipid-rich cell membranes which leads to an accumulation of phospholipids.…”

Section: Introductionmentioning

confidence: 99%

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

Matheis

Gamber

et al. 2010

Experimental and Toxicologic Pathology

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To cite this version:N. Ozaki, K.A. Matheis, M. Gamber, T. Feidl, T. Nolte, et al.. Identification of genes involved in gentamicin induced nephrotoxicity in rats-a toxicogenomic investigation. Experimental and Toxicologic Pathology, Elsevier, 2010, 62 (5) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t

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Section: Introductionmentioning

confidence: 99%

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

Matheis

Gamber

et al. 2010

Experimental and Toxicologic Pathology

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“…In rats treated with low doses of gentamicin (<20 mg/kg), histologically confirmed necrosis is infrequently encountered and animals show no alteration of renal function. A conspicuous lysosomal phospholipidosis is seen in proximal tubular cells under these experimental conditions (12,18,19), but its relationship to tubular necrosis and renal dysfunction remains to be elucidated (19,22,27).…”

mentioning

confidence: 96%

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

Laurent¹,

Maldague²,

Carlier³

et al. 1983

Antimicrob Agents Chemother

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Kidney cortex DNA synthesis was studied in female rats treated with a low dose of gentamicin (10 mg/kg) up to 14 days. Synthesis was measured by incorporation of [3H]thymidine into DNA 1 h after intraperitoneal injection of the labeled precursor (200 muCi per animal). Gentamicin given in one injection per day resulted in a greater incorporation of [3H]thymidine into DNA after both 7 and 14 days of treatment as compared with control animals. When the daily dose was divided into three equal injections given at 8-h intervals, a statistically significant increase in thymidine incorporation was observed as early as 4 days after starting gentamicin administration. Excellent agreement was found between DNA specific radioactivity and kidney cortex nuclear labeling, as measured by histoautoradiography. The greatest amount of [3H]thymidine incorporation occurred within proximal tubular cells and interstitial cells. We conclude that a finite duration of gentamicin treatment at low dosage induces an increased DNA synthesis in vivo in rat kidney cortex. We suggest that this reaction results from cellular proliferation and could reflect a regenerative process after focal necrosis induced by gentamicin at low doses. The demonstrated early increase in DNA synthesis could be a useful tool to measure kidney cortex alterations caused by various aminoglycosides at low, therapeutic doses.

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“…Only one kidney was used per animal, since it has been shown that the rate of DNA synthesis is similar in both kidneys of the same animal (10,18). Sphingomyelinase (EC 3.1.4.12) activity and total phospholipids were assayed in the cortex of each right kidney by previously published procedures (17).…”

Section: Methodsmentioning

confidence: 99%

“…These primary lysosomes transfer the aminoglycoside to secondary lysosomes, where storage occurs independently of the duration of treatment (11). These drugs induce a lysosomal phospholipidosis characterized by inhibition of sphingomyelinase and phospholipase A1 activity and by phospholipid accumulation into lysosomes (17). This lysosomal phospholipidosis is accompanied by cellular necrosis and postnecrotic cell regeneration (10,18,20).…”

mentioning

confidence: 99%

Influence of Hydrocortisone on Gentamicin-Induced Nephrotoxicity in Rats

Beauchamp¹,

Pettigrew²

1989

The Pediatric Infectious Disease Journal

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Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of steroids has never been investigated. We evaluated the role of hydrocortisone on gentamicin-induced nephroxicity in a model of infused rats. We showed that hydrocortisone given over 3 days after the infusion did not modify the gentamicin half-life in the renal cortex, gentamicin-induced lysosomal phospholipidosis, or histopathology but did reduce significantly the 3H/DNA ratio on day 4 after gentamicin infusion. We concluded that hydrocortisone interferes with the postnecrotic cellular regeneration process, an important step that is responsible for the recovery of normal kidney structure and function following toxic injuries associated with aminoglycoside therapy.Eliminated essentially by glomerular filtration, aminoglycosides are partially reabsorbed by proximal tubular cells through absorptive endocytosis (pinocytosis) into small vesicles that fuse with primary lysosomes (11, 28). These primary lysosomes transfer the aminoglycoside to secondary lysosomes, where storage occurs independently of the duration of treatment (11). These drugs induce a lysosomal phospholipidosis characterized by inhibition of sphingomyelinase and phospholipase A1 activity and by phospholipid accumulation into lysosomes (17). This lysosomal phospholipidosis is accompanied by cellular necrosis and postnecrotic cell regeneration (10,18,20).Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans. They are an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of treatment, and liver disease (23,26). In animals, dose and frequency (4), age (21, 22), sex (3,15), concomitant use of vancomycin (32), and renal infections (2) are clearly recognized as risk factors. The role of antiinflammatory agents like hydrocortisone on aminoglycoside nephrotoxicity is unknown. Steroids and nonsteroidal antiinflammatory agents are frequently administered with antibiotics to patients suffering from severe localized infections. In addition to their mineral and glucocorticoid effects, it has been shown that steroids suppress DNA synthesis in the livers of growing rats (6, 14) and in various nonlymphoid tissue of the weanling rats (19) and inhibit mitosis in various cells in tissue cultures (12).The objective of the present study was to evaluate the role of hydrocortisone on the pathophysiology of gentamicin nephrotoxicity. Special attention was focused on the effect of hydrocortisone on renal tubular epithelial cells undergoing renewal and repair. MATERIALS AND METHODSFemale Sprague-Dawley rats (weight, between 200 and 250 g) were used in this study. They were housed singly and had free access to food and water throughout the experiment. Gentamicin was infused over a 1...

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Mechanism of aminoglycoside-induced lysosomal phospholipidosis: In vitro and in vivo studies with Gentamicin and Amikacin

Cited by 225 publications

References 33 publications

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

Influence of Hydrocortisone on Gentamicin-Induced Nephrotoxicity in Rats

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