Effects of gentamicin on the renal uptake of endogenous and exogenous proteins in conscious rats

Bernard, Alfred; Viau, Claude; Ouled, A.; Tulkens, Paul M.; Lauwerys, Robert

doi:10.1016/0041-008x(86)90248-6

Cited by 20 publications

(8 citation statements)

References 26 publications

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“…This is consistent with the observation that proteins smaller than 20 kDa have sieving coefficients Ͼ0.5 (22). The high degree of tubular reabsorption of filtered NH 2 -CTGF and low FE are also in accordance with previously observed values for other low molecular mass proteins, e.g., ␤ 2 M (fractional reabsorption 99.97%, FE 0.03%) and lysozyme (FE 0.4%) (3,20,33). Impairment of proximal tubular reabsorption, either induced by Gelofusine administration or in human renal disease, was consistently associated with an increase in uCTGF excretion in close correlation with that of ␤ 2 M. Tubular dysfunction is an important parameter in the assessment of renal damage.…”

Section: Discussionsupporting

confidence: 91%

Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion

Gerritsen¹,

Peters

Nguyen³

et al. 2010

American Journal of Physiology-Renal Physiology

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Connective tissue growth factor (CTGF) plays a key role in renal fibrosis. Urinary CTGF is elevated in various renal diseases and may have biomarker potential. However, it is unknown which processes contribute to elevated urinary CTGF levels. Thus far, urinary CTGF was considered to reflect renal expression. We investigated how tubular dysfunction affects urinary CTGF levels. To study this, we administered recombinant CTGF intravenously to rodents. We used both full-length CTGF and the NH(2)-terminal fragment, since the NH(2)-fragment is the predominant form detected in urine. Renal CTGF extraction, determined by simultaneous arterial and renal vein sampling, was 18 +/- 3% for full-length CTGF and 21 +/- 1% for the NH(2)-fragment. Fractional excretion was very low for both CTGFs (0.02 +/- 0.006% and 0.10 +/- 0.02%, respectively), indicating that >99% of the extracted CTGF was metabolized by the kidney. Immunohistochemistry revealed extensive proximal tubular uptake of CTGF in apical endocytic vesicles and colocalization with megalin. Urinary CTGF was elevated in megalin- and cubilin-deficient mice but not in cubilin-deficient mice. Inhibition of tubular reabsorption by Gelofusine reduced renal uptake of CTGF and increased urinary CTGF. In healthy volunteers, Gelofusine also induced an increase of urinary CTGF excretion, comparable to the increase of beta(2)-microglobulin excretion (r = 0.99). Furthermore, urinary CTGF correlated with beta(2)-microglobulin (r = 0.85) in renal disease patients (n = 108), and only beta(2)-microglobulin emerged as an independent determinant of urinary CTGF. Thus filtered CTGF is normally reabsorbed almost completely in proximal tubules via megalin, and elevated urinary CTGF may largely reflect proximal tubular dysfunction.

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Section: Discussionsupporting

confidence: 91%

Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion

Gerritsen¹,

Peters

Nguyen³

et al. 2010

American Journal of Physiology-Renal Physiology

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“…It is well established that rats with streptozotocin-induced DM exhibit a significant proteinuria compared with nondiabetic animals (26, 27), and that protein excretion increases in nondiabetic rats following the administration of gentamicin (27)(28)(29). In 6-hr perfusion studies in vivo, Pattyn et al (25) demonstrated that the renal cortical uptake of gentamicin was reduced in diabetic rats with modest proteinuria in comparison to control animals.…”

Section: Discussionmentioning

confidence: 96%

Insulin Reverses the Protection Given by Diabetes Against Gentamicin Nephrotoxicity in the Rat

Gouvea

Roth

Alpert

et al. 1994

Experimental Biology and Medicine

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Rats with untreated diabetes mellitus are protected from gentamicin-induced nephrotoxicity. In order to evaluate the role of hyperglycemia, glycosuria, and polyuria in this phenomenon, miniosmotic pumps filled with insulin were implanted for 15 days in seven female Sprague-Dawley rats with streptozotocin-induced diabetes mellitus. Plasma glucose levels were successfully maintained under 126 mg/dl. To serve as the control group, eight age-matched diabetic (plasma glucose > 400 mg/dl) rats had miniosmotic pumps placed delivering only Ringer's solution. Six days after placement of the pumps, gentamicin (40 mg/Kg/day) was administered to all animals for 9 days. The insulin-treated diabetic rats exhibited clear signs of nephrotoxicity by Day 6 of gentamicin, whereas the diabetic control group remained free from any functional or morphological evidence of proximal tubular damage throughout the 9 days of the aminoglycoside administration. At the end of the experiment, the creatinine clearance in the insulin-treated diabetic group was 45% lower than in the untreated diabetic group (P < 0.005). In addition, there was a rise in plasma creatinine (P < 0.02), muramidase appeared in the urine, and mild patchy acute tubular necrosis of the renal cortex was observed by light microscopic examination. The insulin-treated group also accumulated more gentamicin in the renal cortex than the untreated animals (P < 0.005). It is concluded that protection against the nephrotoxic effects of gentamicin is a feature of untreated experimental diabetes mellitus in the rat and that correction of the hyperglycemic state with insulin reverses this resistance.

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“…In particular we do not know if the increase of urinary NAG excretion during netilmicin therapy re flects cell death secondary to lysosomes membranes labilization [36] or if it repre sents a normal process of activated exocytosis by which the proximal cell eliminates intralysosomal accumulated phospholipids. This latter hypothesis has been suggested re cently by Bernard et al [7], Further studies are therefore needed to establish a relation ship belween an increase of lysosomal hy drolases such as NAG and a real dysfunction of the proximal cell metabolism.…”

Section: N-acetyl-beta-z)-glucosaminidase Excretion and Aminoglycosidmentioning

confidence: 95%

“…This binding can be competitively blocked by an increase in ionized calcium [6]. In the same way, aminoglycoside-like gentamicin seems to interfere with proteins reabsorp tion by the kidney which could explain the increase in urinary protein excretion such as betai-microglobulin during antibiotic ther apy [7], An uptake of aminoglycosides has been demonstrated within the proximal tubular cells [8], This uptake occurs predominantly by pinocytosis at the luminal surface. How ever, in vitro studies have recently shown that aminoglycoside transport could also oc cur via the basal lateral membrane and con tribute to the high renal cortical concentra tion of the drug [9].…”

Section: Aminoglycosides: Renal Eliminationmentioning

confidence: 99%

Aminoglycoside Nephrotoxicity and Urinary Excretion of N-Acetyl-Beta-<i>D</i>-Glucosaminidase

Langhendries

Battisti

Bertrand³

1988

Neonatology

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Effects of gentamicin on the renal uptake of endogenous and exogenous proteins in conscious rats

Cited by 20 publications

References 26 publications

Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion

Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion

Insulin Reverses the Protection Given by Diabetes Against Gentamicin Nephrotoxicity in the Rat

Aminoglycoside Nephrotoxicity and Urinary Excretion of N-Acetyl-Beta-<i>D</i>-Glucosaminidase

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