Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model?

Claramunt, Débora; Gil‐Peña, Helena; Fuente, Rocío Aller de la; Hernández-Frías, Olaya; Santos, Fernando

doi:10.1016/j.nefro.2015.08.004

Cited by 21 publications

(15 citation statements)

References 36 publications

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“…In this study, GH was able to raise Aqp1 levels at the prehypertrophic stages and allow chondrocytes to enter hypertrophy with significantly increased levels compared to uremic chondrocytes (cluster 4 to 5), a result that differs from previously published studies [10]. The level of Aqp1 expression in GH-treated chondrocytes, even if significantly lower than the control in most of the GP, has the same pattern of variation across the GP than untreated chondrocytes, indicating that, even though Aqp1 is still functioning, it could not be a part of the mechanism by which GH normalizes the chondrocyte volume in uremic conditions.…”

Section: Discussioncontrasting

confidence: 95%

“…It is of note that a similar degree of growth retardation was found in the AD and PF groups. In this model of uremia, a greater degree of growth impairment in the AD rats could have been achieved by a higher dose of adenine in their diets, as adenine is not well tolerated by rats and causes more severe bone diseases than in rats with subtotal nephrectomy [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

Fernández-Iglesias

Fuente

Gil‐Peña

et al. 2020

IJMS

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Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement.

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Section: Discussioncontrasting

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

Fernández-Iglesias

Fuente

Gil‐Peña

et al. 2020

IJMS

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“…The histopathological findings in the kidneys were in good congruence to those described in the literature [5]; precipitates and crystals occurred in the apical epithelial region of proximal tubules associated with tubular degradation, atrophy, and dilatation. The observed focal degeneration of cardiac tissues and cardiac vasculopathy might be an indicator of increased cardiovascular morbidity in the AD-1K rats that merits further studies directed at reducing CKD-associated cardiovascular mortality.…”

Section: Discussionsupporting

confidence: 85%

A Novel Model of Chronic Kidney Disease in Rats: Dietary Adenine in Combination with Unilateral Nephrectomy

et al. 2019

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Background: Adenine at 0.75% in the diet (AD) triggers renal impairment in rats. This model of kidney disease is largely reversible when AD feeding is stopped. Testing of novel drugs parallel to AD administration may result in unwanted interference. Objectives: We hypothesized that combining AD with unilateral nephrectomy (UNx) would result in progressive chronic kidney disease (CKD) even after cessation of AD. Methods: In an explorative study, 16 rats with UNx (AD-1K rats) and 10 sham-operated rats (AD-2K rats) received AD-supplemented feed for 3 weeks, followed by 4 weeks of standard chow. Ten sham-operated rats receiving only standard chow served as controls. Laboratory parameters in blood and urine were frequently assessed during and after cessation of AD feeding. Comprehensive pathological examinations were performed in all rats at the end of the experiment. Results: Rats with UNx were more affected by impaired glomerular filtration rate, anemia, hyperphosphatemia, and hypocalcemia. After cessation of AD feeding, recovery was poorest in AD-1K rats, paralleled by increased proteinuria indicative of progressive CKD. Scores in histopathological damage of the kidneys indicative of CKD were seen in both AD-fed groups, with key parameters being more affected in AD-1K rats. Histopathological changes in the heart were most prominent in AD-1K rats. Conclusions: Combining AD feeding with UNx provides a time window after cessation of AD feeding for the testing of drugs without interference. Our findings in rats may have implications for research in other target animal species as well.

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“…Adenine model was established mainly in mice or rats and was used to test therapeutic strategies that may slow progression or even reverse renal injury and fibrosis 22 . After oral administration, adenine metabolites precipitates as crystals in renal tubules leading to tubulointerstitial nephritis and vascular calcification as well 23 .…”

Section: Discussionmentioning

confidence: 99%

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

Awad

Saleh

Abu-Elsaad

et al. 2020

Sci Rep

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Renal fibrosis is a failed regenerative process that facilitates chronic kidney disease progression. The current study was designed to study the effect of erlotinib, a receptor tyrosine kinase inhibitor, on the progression of renal fibrosis. The study included four groups of mice: control group; adenine group: received adenine (0.2% w/w) daily with food for 4 weeks; erlotinib group: received 80 mg/ kg/day erlotinib orally (6 ml/kg/day, 1.3% w/v suspension in normal saline 0.9%) for 4 weeks; adenine + erlotinib group: received adenine and erlotinib concurrently. Kidney function and antioxidant biomarkers were measured. Renal expression of Bcl2 and p53 and histopathological changes (tubular injury and renal fibrosis) were scored. Renal tissue levels of transforming growth factor-β 1 , p-ERK1/2 and p-STAT3 were measured. Results obtained showed significant decrease (P < 0.001) in serum creatinine, urea and uric acid in erlotinib + adenine group. Level of malondialdehyde was decreased significantly (P < 0.001) while reduced glutathione and catalase levels were increased (P < 0.01) by erlotinib concurrent administration. Erlotinib markedly reduced fibrosis and tubular injury and decreased TGF-β1, p-ERK1/2 and p-STAT3 (P < 0.5). In addition, expression level of Bcl-2 was elevated (P < 0.001) while that of p53-was reduced compared to adenine alone. Erlotinib can attenuate renal fibrosis development and progression through anti-fibrotic, antioxidant and antiapoptotic pathways. Chronic kidney disease (CKD) is a global health burden and is considered as an independent risk factor for cardiovascular diseases. Its prevalence is correlated to many health problems as diabetes, hypertension and obesity 1, 2. Renal fibrosis is a failed regenerative process that facilitates the development of CKD. The progression of renal insufficiency in patients with CKD is mainly due to tubulointerstitial fibrosis, glomerular inflammation and tubular atrophy 3. Many cellular events are involved in tubulointerstitial fibrosis as infiltration of inflammatory cells, fibroblast activation, extracellular matrix (ECM) deposition and microvascular rarefaction 4. Various mediators are involved in the development of CKD and may represent possible targets for therapy such as transforming growth factor (TGF)-β, nuclear factor-erythroid 2 related factor, peroxisome proliferatoractivated γ receptor, IL-11 and advanced glycation endproducts 5, 6. Recently, studies reported involvement of miRNA in the progression of CKD progression 7. Tyrosine kinases have a pivotal role in cell signalling, and their activity deregulation can promote the development and progression of fibrotic diseases. As a result, pathologic activation of tyrosine kinases can drive fibrogenesis 8. Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, has been identified in renal tissue mainly in the epithelial cells of distal and collecting tubules, peritubular vessels and glomeruli with more abundant expression in diseased than in normal kidneys 9, 10. Activation of these r...

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Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model?

Cited by 21 publications

References 36 publications

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

A Novel Model of Chronic Kidney Disease in Rats: Dietary Adenine in Combination with Unilateral Nephrectomy

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

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