Rapamycin retards growth and causes marked alterations in the growth plate of young rats

Álvarez-García, Óscar; Carbajo-Pérez, E; García, Eva; Gil, Helena; Molinos, Inés; Rodrı́guez, Julián; Ordoñez, Flor A.; Santos, Fernando

doi:10.1007/s00467-007-0456-8

Cited by 60 publications

(77 citation statements)

References 37 publications

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“…In some clinical trials in the past, similar drug concentrations were used successfully. 3 In a recently published experimental model, 22 a high intraperitoneal dosage of 2 mg/kg per d (corresponding to a weekly dosage of 14 mg/kg) was applied. We chose an intermediate dosage corresponding to 3 mg/kg per wk.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

Diekmann¹,

Rovira²,

Carreras³

et al. 2007

Journal of the American Society of Nephrology

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Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor-based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (P Ͻ 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.

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Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

Diekmann¹,

Rovira²,

Carreras³

et al. 2007

Journal of the American Society of Nephrology

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“…Liver samples and the proximal end of right tibias were immediately frozen in liquid nitrogen for mRNA expression studies. Left tibial proximal ends were embedded in methyl-metacrilate as previously described (2,19). Samples from one-half the animals were fixed in 40% ethanol and used for analysis of calcein and BrdU labeling.…”

Section: Methodsmentioning

confidence: 99%

“…Snout-to-tail-tip length of rats was measured at death. The longitudinal bone growth rate (m/day) during the 3 days before death was calculated by means of calcein labeling as previously described (2,19).…”

Section: Methodsmentioning

confidence: 99%

“…For immunohistochemical staining of IGF-I and the IGF-I receptor, rabbit polyclonal anti-rat-specific antibodies (Santa Cruz Biotechnology, Heidelberg, Germany) were used. The immunohistochemical staining followed the procedure is already described in other studies (2,19) with minor modifications. Incubation (30 min at 45°C) in a pepsin solution (5 mg/ml for IGF-I and 10 mg/ml for IGF-I receptor) was used for antigen retrieval.…”

Section: Methodsmentioning

confidence: 99%

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Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

Gil‐Peña¹,

García-López²,

Álvarez-García³

et al. 2009

American Journal of Physiology-Renal Physiology

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of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment. Am J Physiol Renal Physiol 297: F639-F645, 2009. First published July 8, 2009 doi:10.1152/ajprenal.00188.2009.-Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n ϭ 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (ϮSD) being 67. . GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.tubulopathies; chondrocyte; cartilage GROWTH RETARDATION IS FREQUENTLY found in primary hypokalemic tubular disorders (32). Potential pathogenic factors of growth impairment in these tubulopathies include maintained metabolic acidosis, polyuria with decreased food intake and repeated dehydration episodes, disturbed bone mineralization, sodium deficit, and potassium depletion. In children with renal tubular acidosis, growth retardation is common and is ameliorated or reversed after sustained correction of metabolic acidosis (29). Metabolic acidosis disturbs normal growth through various mechanisms such as the stimulation of protein catabolism (18), interference with growth hormone (GH) action (21), and the alteration of the structure and dynamics of growth cartilage (5). In hypokalemic tubulopathies associated with alkalosis, Bartter's or Gitelman's syndromes, the adverse effect on growth is not well documented and the response of growth to treatment is rather unpredictable. Growth impairment is frequently described in Bartter's syndrome (22). Gitelman's syndrome, traditionally considered as asymptomatic or responsible for mild clinical manifestations (9), has been reported to be accompanied by short stature in over 30% of children (8).Although clinical cases of isolated GH deficiency as well as improvement of growth rate following administration of indomethacin have been reported in patients with Gitelman's syndrome, the...

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“…This potent inhibition of mTOR is likely to account for the cytostatic effects of BEZ235 on MSC growth observed at higher concentrations, given the well-established role of mTOR signaling in regulating protein synthesis. (52,53) To date, the role of mTOR in osteogenesis remains controversial because conflicting studies using rapamycin have reported both negative (54)(55)(56)(57)(58)(59) and positive (24)(25)(26) effects on osteogenesis.…”

Section: Nvp-bez235 Promotes Osteogenesis In Human Mscsmentioning

confidence: 99%

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

Martin¹,

Fitter²,

Bong³

et al. 2010

Journal of Bone and Mineral Research

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Osteoblasts are bone-forming cells derived from mesenchymal stromal cells (MSCs) that reside within the bone marrow. In response to a variety of factors, MSCs proliferate and differentiate into mature, functional osteoblasts. Several studies have shown previously that suppression of the PI3K and mTOR signaling pathways in these cells strongly promotes osteogenic differentiation, which suggests that inhibitors of these pathways may be useful as anabolic bone agents. In this study we examined the effect of BEZ235, a newly developed dual PI3K and mTOR inhibitor currently in phase I-II clinical trials for advanced solid tumors, on osteogenic differentiation and function using primary MSC cultures. Under osteoinductive conditions, BEZ235 strongly promotes osteogenic differentiation, as evidenced by an increase in mineralized matrix production, an upregulation of genes involved in osteogenesis, including bone morphogenetic proteins (BMP2, -4, and -6) and transforming growth factor b1 (TGF-b1) superfamily members (TGFB1, TGFB2, and INHBE), and increased activation of SMAD signaling molecules. In addition, BEZ235 enhances de novo bone formation in calvarial organotypic cultures. Using pharmacologic inhibitors to delineate mechanism, our studies reveal that suppression of mTOR and, to a much lesser extent PI3K p110a, mediates the osteogenic effects of BEZ235. As confirmation, shRNA-mediated knockdown of mTOR enhances osteogenic differentiation and function in SAOS-2 osteoblast-like cells. Taken together, our findings suggest that BEZ235 may be useful in treating PI3K/mTOR-dependent tumors associated with bone loss, such as the hematologic malignancy multiple myeloma. ß

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Rapamycin retards growth and causes marked alterations in the growth plate of young rats

Cited by 60 publications

References 37 publications

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells

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