Alterations of tubules and glomerules have been reported previously in kidneys of rat neonates after aminoglycosides were given to the mother during gestation. Here, we have studied the effects of gentamicin on the development of the glomerular basement membrane (GBM). Pregnant Wistar female rates were treated with gentamicin. Deliveries occurred normally. Using electron microscopy, we looked at the deepest glomerules of the kidneys of 1-day-old neonates: myeloid bodies were found in podocytes, and the GBM appeared thicker and denser than in controls. Anionic ferritin, injected intravenously crossed the GBM in prenatally gentamicin-exposed animals, but not in controls. Furthermore, urine electrophoresis showed the presence of proteins normally found only in the urine of fetuses 2 days before birth. We suggest then, that in utero exposure to gentamicin leads to a delay of renal maturation and that the GBM is altered in juxtamedullary nephrons while it is normally differentiated and functioning in controls. Thus exposure to drugs before birth could be harmful to the GBM.
Gentamicin during gestation alters glomerular basement membrane development. A drug-induced nephrotoxicity was described for neonates after gentamicin was given intraperitoneally to pregnant Wistar rats; glomerular alterations and changes in permselectivity were important. We investigated the ultrastructure of the glomerular basement membrane (GBM), the arrangement of anionic sites, and the urinary proteins at two ages, with 1-day-and 12-month-old control and prenatally exposed animals. For neonates, the pattern of glomerular differentiation was similar, anionic sites were made of heparan sulfate proteoglycans, and the GBM had the same total thickness in both groups. After transplacental gentamicin exposure, the lamina densa was larger, the laminae rarae were thinner, the density of anionic sites was increased; the levels of hydroxyproline, sulfate, and hexuronic acid in the kidney were increased; and the immunoelectrophoresis of urinary proteins was abnormal. For adults, prenatal exposure to gentamicin led to altered juxta-medullary glomeruli with a larger GBM and abundant anionic sites, especially in the lamina densa, and to a protein excretion different from that of controls. Thus, gentamicin administered during pregnancy leads to permanent alterations of the GBM with modifications of both the layers and the anionic sites, possibly because of a perturbed protein metabolism. These altered glomeruli are at risk during life and could be the starting point for a kidney disease.Analysis of drugs in relation to their safety for mother and fetus is usually restricted to gross examinations of the newborn alone. The developing kidney, considered to be resistant to nephrotoxicity (17), is rarely investigated despite the fact that renal alterations in young and puppies have been described after administration of different drugs (18,37). Only recently has there begun to emerge a perception of how alterations of the developing kidney could explain a large variety of renal disorders, especially glomerular ones (3,44,50).In contrast, for adults nephrotoxicity studies have been expanding for 2 decades mainly because kidney diseases constitute an important economic burden which could be relieved in part by prevention. Following the widespread use of aminoglycoside antibiotics, gentamicin-induced nephrotoxicity became one of the most investigated drug-induced renal injuries (7,22,24,29,43).Observations of in utero aminoglycoside-induced nephrotoxicity after antibiotics had been given to pregnant rats (20,21,(31)(32)(33) showed that, contrary to what is seen with adults, glomerular modifications are very common while tubules are less altered. Also, an abnormal proteinuria was described and a marker with a high molecular weight (anionic ferritin) was found in the urine and glomerular podocytes after being injected intravenously into neonates (42), indicating an altered permselectivity of the glomerular basement membrane (GBM) of the mature glomeruli.Renal maturation, similar in all mammals, is often termi-* Corresponding author....
Changes in kidney maturation in utero have been reported after gentamicin administration to pregnant rats. While the proteinuria commonly observed could be related to modifications of the glomerular basement membrane, perturbed renal protein handling could be accounted for by changes in the proximal tubular cells. Therefore, we studied the effect of gentamicin on the renal handling and transport of proteins in proximal tubular cells using the horseradish peroxidase, a fluid-phase marker, as a probe. Gentamicin was administered intraperitoneally to pregnant Wistar rats (75 mg/kg body weight per day) and neonatal kidneys were studied 1 day after birth. In proximal tubular cells of the deep cortical area, containing the fully matured nephrons of neonates, the transport and digestion of reabsorbed peroxidase was considerably reduced compared with controls where peroxidase reached lysosomes after endocytosis. Urinary protein excretion increased in treated animals. We conclude that gentamicin, entering the proximal tubular cells via the endocytic pathway, decreases the tubular reabsorption of proteins, thus increasing urinary protein excretion.
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