Neonatal Dexamethasone Treatment in the Rat Leads to Kidney Damage in Adulthood

Vries, Willem B. de; Borne, Pleunie van den; Goldschmeding, Roel; Weger, Roel A. de; Bal, Miriam P; Bel, Frank van; Oosterhout, Matthijs F.M. van

doi:10.1203/pdr.0b013e3181bf570d

Cited by 25 publications

(20 citation statements)

References 26 publications

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“…Moreover, kidney function in L-CAR ϩ 1 ⁄2DEX rats was not worse than in 1 ⁄2DEX rats and still better than the kidney function after full DEX treatment. The latter is significantly worse than all other treatment regimes, as shown in this study, a previous one (9), which was recently confirmed (39). Thus, neonatal DEX treatment in rats leads to kidney damage in later life, and this effect is dose dependent, i.e.…”

Section: Discussionsupporting

confidence: 87%

Long-Term Effects of Neonatal Treatment With Dexamethasone, l-Carnitine, and Combinations Thereof in Rats

Yan

Leij

2011

Pediatr Res

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Because L-carnitine (L-CAR) is a potential substitute for neonatal dexamethasone (DEX) with respect to the prevention of long-term side effects, rats were treated on d 1, 2, and 3 after birth with saline, DEX, L-CAR, half the dose of DEX, and L-CAR ϩ half DEX. DEX led to growth retardation, increased mortality, and severe kidney damage at 50 wk of age. L-CAR had no negative effects on growth, kidney function at 50 wk, and survival at 101 wk. Growth retardation was induced transiently by half DEX and permanently by L-CAR ϩ half DEX, slightly reduced kidney function but no reduced life span was found in both these groups. Except for the DEX group, blood glucose levels were normal at 50 wk in all groups. A serendipitous finding was that L-CAR treatment caused one-third less food intake; however, these rats maintained normal body weight. In conclusion, L-CAR, a lower dose of DEX, and their combination caused less negative effects in later life. Because L-CAR ϩ half DEX had a negative effect on growth, attention to monitor L-CAR levels during DEX treatment of preterm newborns seems to be justified. The finding that neonatal L-CAR caused reduced food intake in later life warrants further investigation. (Pediatr Res 69: 148-153, 2011)

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Section: Discussionsupporting

confidence: 87%

Long-Term Effects of Neonatal Treatment With Dexamethasone, l-Carnitine, and Combinations Thereof in Rats

Yan

Leij

2011

Pediatr Res

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“…However, maternal treatment with dexamethasone during pregnancy has also been shown to program kidney development (5,35) and has an effect on renal tubular transporters (36,37). This has resulted in a widely used model in the study for the developmental origins of health and disease (5).…”

Section: Drugs Disturbing Renal Developmental Factorsmentioning

confidence: 99%

Effect of Drugs on Renal Development

Schreuder¹,

Bueters²,

Huigen³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryMany nephrotoxic effects of drugs have been described, whereas the effect on renal development has received less attention. Nephrogenesis ceases at approximately 36 weeks of gestation, indicating that drugs administered to pregnant women and to preterm-born neonates may influence kidney development. Such an effect on renal development may lead to a wide spectrum of renal malformations (congenital anomalies of the kidney and urinary tract [CAKUT]), ranging from renal agenesis to a reduced nephron number. Any of these anomalies may have long-term sequelae, and CAKUT is the primary cause for renal replacement therapy in childhood. This review focuses on research into the effect of drug treatment during active nephrogenesis during pregnancy and in preterm-born infants. Because the effects of many widely used drugs have not been unraveled thus far, more research is needed to study the effect on renal development and long-term renal sequelae after drug treatment during nephrogenesis.

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“…However, a rapid nongenomic GR-initiated up-regulation that does not involve increases in protein abundance also occurs (Wang et al, 2007). Moreover, maternal treatment with dexamethasone during pregnancy reduces kidney development in the young (de Vries et al, 2010) and stimulates renal tubular NHE activity (Dagan et al, 2007), effects that possibly relate to development of hypertension in adult life.…”

Section: Abbreviationsmentioning

confidence: 99%

Rapid, Nongenomic Stimulation of Multidrug Resistance Protein 2 (Mrp2) Activity by Glucocorticoids in Renal Proximal Tubule

Prevoo

Miller²,

Water³

et al. 2011

J Pharmacol Exp Ther

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In renal proximal tubule, multidrug resistance protein 2 (Mrp2) actively transports many organic anions into urine, including drugs and metabolic wastes. Upon exposure to nephrotoxicants or during endotoxemia, both Mrp2 activity and expression are up-regulated. This may result from induced de novo synthesis of Mrp2 or post-transcriptional events involving specific signaling pathways. Here, we investigated glucocorticoid signaling to Mrp2 in killifish renal proximal tubules, a model system in which transport activity can be measured using a fluorescent substrate and confocal imaging. Exposure of tubules to dexamethasone rapidly increased Mrp2-mediated fluorescein methotrexate transport. Other glucocorticoid receptor (GR) ligands, cortisol and triamcinolone acetonide, also stimulated Mrp2-mediated transport. The GR antagonist, mifepristone 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl] estra-4,9-dien-3-one (RU486), abolished stimulation by all three ligands, whereas the mineralocorticoid receptor antagonist, spironolactone, was ineffective. Consistent with action through a nongenomic mechanism, dexamethasone stimulation of Mrp2-mediated transport was insensitive to cycloheximide and actinomycin D, and immunohistochemistry revealed no alterations in Mrp2 expression at the luminal membrane. (9S-(9␣,10␤,12␣))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3Ј,2Ј,1Ј-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one (K252a), an inhibitor of the tyrosine receptor kinase subfamily, reduced the dexamethasone effect, as did the specific hepatocyte growth factor receptor (c-Met) tyrosine kinase inhibitor, -665752). Hepatocyte growth factor (HGF), an endogenous ligand for c-Met, stimulated Mrp2-mediated transport. This effect was reversed by PHA-665752 but not by RU486. Inhibition of mitogenactivated protein kinase/extracellular signal-regulated kinase kinase (MEK 1/2) also abolished the effects of dexamethasone and HGF. Our results disclose a novel mechanism by which glucocorticoids acting through GR, c-Met, and MEK1/2 cause rapid, nongenomic stimulation of Mrp2-mediated transport in renal proximal tubules. This up-regulation may be nephroprotective, enhancing efflux of metabolic wastes and toxicants during cell and tissue stress.

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Neonatal Dexamethasone Treatment in the Rat Leads to Kidney Damage in Adulthood

Cited by 25 publications

References 26 publications

Long-Term Effects of Neonatal Treatment With Dexamethasone, l-Carnitine, and Combinations Thereof in Rats

Long-Term Effects of Neonatal Treatment With Dexamethasone, l-Carnitine, and Combinations Thereof in Rats

Effect of Drugs on Renal Development

Rapid, Nongenomic Stimulation of Multidrug Resistance Protein 2 (Mrp2) Activity by Glucocorticoids in Renal Proximal Tubule

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