Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition

Lasaitiene, Daina; Chen, Yun; Guron, Gregor; Marcussen, Niels; Tarkowski, Andrzej; Telemo, Esbjörn; Friberg, Peter

doi:10.1093/ndt/gfg447

Cited by 30 publications

(32 citation statements)

References 19 publications

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“…22,23 Tubulointerstitial damage found in the ARA-treated rats was expected, because it is well established that blockade of RAS during nephrogenesis results in tubular dilatation, chronic interstitial inflammation, and fibrosis in the adulthood 9 and that tubular dilatation is an early event followed by a secondary inflammatory response. 24 It is clear that tubulointerstitial injury in the renal cortex and renal medulla was also greater in males than in females, with a similar decrease in nephron number. In support of our results, Mulroney et al 23 reported that tubular lesions in rats are greater in males than in females 8 to 10 weeks after uninephrectomy.…”

Section: Discussionmentioning

confidence: 96%

Sex Differences in the Renal Changes Elicited by Angiotensin II Blockade During the Nephrogenic Period

et al. 2007

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Abstract-The renin-angiotensin system plays an important role in renal development. However, it is unknown whether reduction in angiotensin II effects during the nephrogenic period leads to different renal alterations in males and females during the adult age. The aim of this study was to evaluate whether the role of angiotensin II on renal development is sex dependent and whether there are sex differences in blood pressure, renal hemodynamics, and severity of renal damage during adult life when nephrogenesis is altered by blocking angiotensin II effects. Newborn Sprague-Dawley rats were treated with an angiotensin II type 1 receptor antagonist (L-158.809; 7 mg/kg per day) during the first 2 weeks of life. At 3 months of age, changes in blood pressure, albuminuria, and renal hemodynamics were assessed, and stereological and histopathologic studies were performed. Blood pressure increased (127Ϯ0.5 versus 115Ϯ0.7 mm Hg in control rats; PϽ0.05) and nephron number decreased (37%; PϽ0.05) similarly in treated males and females. However, only males had an elevation in albuminuria (5.92Ϯ1.65 versus 0.33Ϯ0.09 mg per day in control rats; PϽ0.05), a fall in glomerular filtration rate (12.6%; PϽ0.05), and a significant decrease in papillary volume (42%; PϽ0.05). Mean glomerular volume, glomerulosclerosis, arteriolar hypertrophy, and tubulointerstitial damage in cortex and medulla were also higher (PϽ0.05) in angiotensin II type 1 receptor antagonist-treated males than in treated females. The results of this study suggest that females seem to be more protected than males to the renal consequences of reducing angiotensin II effects during renal development.

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Section: Discussionmentioning

confidence: 96%

Sex Differences in the Renal Changes Elicited by Angiotensin II Blockade During the Nephrogenic Period

et al. 2007

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“…Glomerular tubular development occurs from 24 wk gestation and is complete at 36 wk (10 -12). In the rat model, glomerulogenesis continues after birth until 14 d of life (13). At birth the neonatal rat kidney is similar to that of a 24-wk gestation human fetus.…”

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confidence: 99%

Renal Glomeruli and Tubular Injury Following Indomethacin, Ibuprofen, and Gentamicin Exposure in a Neonatal Rat Model

et al. 2007

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Indomethacin, ibuprofen, and gentamicin are commonly administered to neonates between 24 and 28 wk gestation when glomerulogenesis is still occurring. Indomethacin is known to cause renal failure in up to 25% of infants treated. Possible morphologic effects of these drugs are largely unknown. The purpose of this study was to determine the type of renal changes found on light (LM) and electron microscopy (EM) following administration of indomethacin, ibuprofen, and gentamicin in a neonatal rat model. Rat pups were exposed to indomethacin or ibuprofen and/or gentamicin antenatally for 5 d before birth or postnatally for 5 d from d 1 of life. Pups were killed at 14 d of age. LM examination in all indomethacin-and ibuprofen-treated pups both antenatally and postnatally showed vacuolization of the epithelial proximal tubules, interstitial edema, intratubular protein deposition but no significant glomerular changes. EM examination showed pleomorphic mitochondria and loss of microvilli in the tubules. The glomeruli showed extensive foot process effacement and irregularities of the glomerular basement membrane. EM changes were most marked in pups treated antenatally with ibuprofen, and indomethacin with gentamicin postnatally. Indomethacin, ibuprofen, and gentamicin cause significant change in glomerular and tubular structure in the neonatal rat model. U p to 5% of infants are delivered between 24 and 28 wk gestation, at a time when glomerulogenesis is occurring. Indomethacin and ibuprofen are commonly used in extremely premature neonates to close a patent ductus arteriosus at this time (1,2). Both of these drugs are successful in closing the ductus (3,4), but the morphologic effects these drugs may have on the developing kidney are unknown. Both drugs are known to be nephrotoxic, with indomethacin causing acute renal failure in 25% of premature neonates treated (5). Ibuprofen is considered to have less renal toxicity than indomethacin, but is as efficacious as indomethacin at closing the patent ductus (6). Two animal studies have shown an effect on glomerulogenesis by ibuprofen and a COX-2 selective inhibitor. In both studies, the number and size of glomeruli was decreased (7,8).Gentamicin is frequently administered at the same time as indomethacin or ibuprofen. Gentamicin has been shown in in vitro studies to affect nephron development (9). The combination of nonsteroidal anti-inflammatory drugs (NSAID) and gentamicin on glomerular development is unknown. The renal effect of indomethacin has not been examined in a neonatal animal model, nor has the combination of both indomethacin or ibuprofen and gentamicin.In the human, glomerulogenesis is complete at 36 wk gestation. The metanephron develops at 5 wk gestation, with vesicular glomeruli development occurring at 18 wk gestation. Glomerular tubular development occurs from 24 wk gestation and is complete at 36 wk (10 -12). In the rat model, glomerulogenesis continues after birth until 14 d of life (13). At birth the neonatal rat kidney is similar to that of a ...

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“…Glomerular tubular development occurs from 24 wk gestation and is complete at 36 wk (1,27,42). In the rat, glomerulogenesis continues after birth for ϳ1 wk (36). Accelerated nephrogenesis and abnormal glomerular morphology have been noted in the premature human neonatal kidney (52).…”

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confidence: 99%

Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat

Kent

Koina

Gubhaju

et al. 2014

American Journal of Physiology-Renal Physiology

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Indomethacin and ibuprofen are administered to close a patent ductus arteriosus (PDA) during active glomerulogenesis. Light and electron microscopic glomerular changes with no change in glomerular number were seen following indomethacin and ibuprofen treatment during glomerulogenesis at 14 days after birth in a neonatal rat model. This present study aimed to determine whether longstanding renal structural changes are present at 30 days and 6 mo (equivalent to human adulthood). Rat pups were administered indomethacin or ibuprofen antenatally on days 18 -20 (0.5 mg·kg Ϫ1 ·dose Ϫ1 indomethacin; 10 mg·kg Ϫ1 ·dose Ϫ1 ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg Ϫ1 ·dose Ϫ1 indomethacin; 10 mg·kg Ϫ1 ·dose Ϫ1 ibuprofen). Control groups received no treatment or normal saline intraperitoneally. Pups were killed at 30 days of age and 6 mo of age. Tissue blocks from right kidneys were prepared for light and electron microscopic examination, while total glomerular number was determined in left kidneys using unbiased stereology. Eight pups were included in each group from 14 maternal rats. At 30 days and 6 mo, there were persistent electron microscopy abnormalities of the glomerular basement membrane in those receiving postnatal indomethacin and ibuprofen. There were no significant light microscopy findings at 30 days or 6 mo. At 6 mo, there were significantly fewer glomeruli in those receiving postnatal indomethacin but not ibuprofen (P ϭ 0.003). In conclusion, indomethacin administered during glomerulogenesis appears to reduce the number of glomeruli in adulthood. Alternative options for closing a PDA should be considered including ibuprofen as well as emerging therapies such as paracetamol. kidney; glomerular number; indomethacin; ibuprofen; premature neonate; fetus INDOMETHACIN MAY BE ADMINISTERED to a pregnant woman as a tocolytic to prevent preterm delivery. Adverse effects of indomethacin on the fetus and neonate have been described including oligohydramnios, persistent renal insufficiency, gastrointestinal bleeding and perforation, and persistent pulmonary hypertension (8,11,21,54,58). It has not been determined whether there is any long-term effect on fetal glomerular development or glomerular endowment following exposure to intrauterine indomethacin.Indomethacin and ibuprofen have been shown to close a patent ductus arteriosus (PDA). The timing of administration of these medications is during a time of active glomerulogenesis (15,16,41,59). Indomethacin is known to be nephrotoxic causing acute renal failure in 25% of premature neonates treated for a PDA (2). Ibuprofen is felt to be less renal toxic than indomethacin, but it is as efficacious as indomethacin at closing the patent ductus (45). Two animal studies have shown an effect on glomerulogenesis (induction of new nephrons and glomeruli) in the rat and mouse with ibuprofen and a cyclooxygenase-2 (COX-2)-selective inhibitor. In both studies, the number and size of glomeruli were decreased (3, 34). Administration of indomet...

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Perturbed medullary tubulogenesis in neonatal rat exposed to renin-angiotensin system inhibition

Abstract: Neonatal ACE inhibition perturbs medullary tubulogenesis, as indicated by tubular dilatation and a lack of E-cadherin expression in these tubules. Macrophage/monocyte-mediated immune response is a secondary event, coincidentally associated with the up-regulation of TNF-alpha.

Cited by 30 publications

References 19 publications

Sex Differences in the Renal Changes Elicited by Angiotensin II Blockade During the Nephrogenic Period

Sex Differences in the Renal Changes Elicited by Angiotensin II Blockade During the Nephrogenic Period

Renal Glomeruli and Tubular Injury Following Indomethacin, Ibuprofen, and Gentamicin Exposure in a Neonatal Rat Model

Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat

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