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Characterization of N-diethylnitrosamine-initiated and ferric nitrilotriacetate-promoted renal cell carcinoma experimental model and effect of a tamarind seed extract against acute nephrotoxicity and carcinogenesis

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Abstract

Renal cell carcinoma (RCC), the commonest malignancy in adult kidney, lacks of early signs, resulting often in metastasis at first diagnosis. N-Diethylnitrosamine (DEN)-initiated and ferric nitrilotriacetate (FeNTA)-promoted RCC may be a useful experimental model, but it is not well characterized. In this study, histological alterations and oxidative stress markers were analyzed at different times throughout RCC development, histological subtype was re-evaluated in the light of current classification, and a tamarind seed extract (TSE) effect was examined. Male Wistar rats experimental groups were control, TSE, DEN, DEN+FeNTA, and TSE+DEN+FeNTA. TSE was given 2 weeks before DEN administration (200 mg/kg) and throughout the experiment. Fourteen days after DEN treatment, two FeNTA doses (9 mg Fe/kg) for acute nephrotoxicity study, and increasing FeNTA doses (3–9 mg Fe/kg) twice a week for 16 weeks for carcinogenesis protocol, were administered. In acute study, necrosis and renal failure were observed and TSE ameliorated them. Throughout carcinogenesis protocol, preneoplastic lesions were observed since 1 month of FeNTA treatment, which were more evident at 2 months, when also renal cysts and RCC were already detected. RCC tumors were obtained without changes in renal function, and clear cell histological subtype was identified in all cases. 4-Hydroxy-2-nonenal and 3-nitro-l-tyrosine levels increased progressively throughout protocol. TSE decreased both oxidative stress markers and, although there was no statistical difference, it delayed RCC progress and decreased its incidence (21 %). This study brings an insight of the time course events in this carcinogenesis model, identifies clear cell subtype and establishes TSE renoprotective effects.

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Abbreviations

BUN:

Blood urea nitrogen

ccRCC:

Clear cell RCC

DEN:

N-Diethylnitrosamine

EDTA:

Ethylenediaminetetraacetic acid

FOX:

Ferrous ion oxidation-xylenol orange

FeNTA:

Ferric nitrilotriacetate

4-HNE:

4-Hydroxy-2-nonenal

H&E:

Hematoxylin and eosin

MDA:

Malondialdehyde

3-NT:

3-Nitro-l-tyrosine

PBS:

Phosphate buffered saline

RCC:

Renal cell carcinoma

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

TSE:

Tamarind seed extract

UICC:

Union Internationale Contre le Cancer

WHO:

World Health Organization

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Acknowledgments

This study was supported by Universidad Nacional Autónoma de México-Dirección General de Asuntos del Personal Académico-Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (UNAM-DGAPA-PAPIIT) under projects IN214307 and IN227010; by Consejo Nacional de Ciencia y Tecnología (CONACYT) 81026 and PAIP 6190-10 given to MEIR. CYVO and FAAA received a fellowship from CONACYT. The authors appreciate the collaboration of M. V. Z. Lucía Macías Rosales for her valuable assistance in animal care and treatment. The funding sponsors had no involvement in this study design, the data collection, analysis and interpretation, the manuscript writing, or the decision to submit the manuscript for publication.

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The authors declare that they have no competing interests.

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Correspondence to María Elena Ibarra-Rubio.

Electronic supplementary material

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Online Resource 1

Concentration response curve for superoxide radical scavenging activity of tamarind seed extract (TSE). Tamarind seed extract scavenging capacity (IC50 = 30.7 ± 0.5 μg gallic acid equivalents/mL), determined by xanthine/xanthine oxidase method, was greater than Vitamin C used as reference compound (IC 50 = 66.0 ± 0.4 μg/mL). Data are expressed as percentage of superoxide radical scavenging activity (PPTX 74 kb)

Online Resource 2

Malondialdehyde (MDA), protein carbonyl content and hydrogen peroxide levels from acute nephrotoxicity study. Renal cortex samples were obtained 24 h after second 9 mg Fe/kg bw FeNTA injection. There were no statistical changes (p > 0.05). Columns represent the mean ± SEM of number of animals indicated below columns (PPTX 133 kb)

Online Resource 3

Determinations along carcinogenesis protocol. a Body weight. Similar increases were observed in control and TSE groups. In DEN group this parameter decreased immediately after its administration but it was reestablished thereafter. Groups treated with FeNTA showed also a decrease but they did not reach control values at the end of the study (p < 0.05). Each point represents the mean value; SEM was omitted to appreciate clearly the behavior of the different groups. Number of animals (from 10 to 25) changed due to mortality. b Renal function evaluation as blood urea nitrogen (BUN) levels throughout carcinogenesis protocol. Several serum samples were taken as described in the text. There were no statistical changes in any group at any time (p > 0.05). Columns in graphs represent the mean ± SEM (PPTX 224 kb)

Online Resource 4

Representative kidney sections with tumor exhibiting different Fuhrman grades induced in DEN+FeNTA group. Grading is dependent solely on nuclear morphology and content and prominence of nucleoli: Grade 1, nuclei are similar to those of normal proximal tubular epithelia and sometimes show pyknosis (with small lymphocyte-like nuclei); grade 2, nuclei are larger than those of grade 1, sometimes show irregularity or slight pleomorphism, often have prominent nucleoli, but are neither evidently atypical nor bizarre; grade 3, nuclei reveal prominent irregularity and pleomorphism and many bizarre or giant nuclei are observed; grade 4, large and pleomorphic nuclei as well as sarcomatoid features are present (description from Thomas, 2008). (H&E, × 100) (PPTX 615 kb)

Online Resource 5

Serum lipid peroxidation 1 h after the 26th injection of FeNTA treatment (9 mg Fe/kg bw). These results suggest that oxidative stress is induced after each FeNTA administration during the development of carcinogenesis protocol and that TSE partially diminishes this parameter in TSE+DEN+FeNTA group. Columns in graphs represent the mean ± SEM. Columns with different letters exhibit statistical difference (p < 0.0262) (PPTX 87 kb)

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Vargas-Olvera, C.Y., Sánchez-González, D.J., Solano, J.D. et al. Characterization of N-diethylnitrosamine-initiated and ferric nitrilotriacetate-promoted renal cell carcinoma experimental model and effect of a tamarind seed extract against acute nephrotoxicity and carcinogenesis. Mol Cell Biochem 369, 105–117 (2012). https://doi.org/10.1007/s11010-012-1373-0

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