Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates

Bishop, A. C.; Spradling-Reeves, K. D.; Shade, R.; Lange, K. J.; Birnbaum, S.; Favela, K.; Dick, E. J.; Nijland, M. J.; Li, C.; Nathanielsz, P. W.; Cox, L. A.

doi:10.1101/2020.12.01.406355

bioRxiv · 10.1101/2020.12.01.406355

Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates

Bishop, A. C.·Spradling-Reeves, K. D.·Shade, R.·Lange, K. J.·Birnbaum, S.·Favela, K.·Dick, E. J.·Nijland, M. J.·Li, C.·Nathanielsz, P. W.·Cox, L. A.

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Abstract

BackgroundPoor nutrition during development programs kidney function. No studies on postnatal consequences of decreased perinatal nutrition exist in nonhuman primates (NHP) for translation to human renal disease. Our baboon model of moderate maternal nutrient restriction (MNR) produces intrauterine growth restricted (IUGR) and programs renal fetal phenotype. We hypothesized that the IUGR phenotype persists postnatally, influencing responses to a high-fat, high-carbohydrate, high-salt (HFCS) diet. MethodsPregnant baboons ate chow (Control; CON) or 70% of control intake (MNR) from 0.16 gestation through lactation. MNR offspring were IUGR at birth. At weaning, all offspring (CON and IUGR females and males, n=3/group) ate chow. At ~4.5 years of age, blood, urine, and kidney biopsies were collected before and after a 7-week HFCS diet challenge. Kidney function, unbiased kidney gene expression, and untargeted urine metabolomics were evaluated. ResultsIUGR female and male kidney transcriptome and urine metabolome differed from CON at 3.5 years, prior to HFCS. After the challenge, we observed sex-specific and fetal exposure-specific responses in urine creatinine, urine metabolites, and renal signaling pathways. ConclusionsWe previously showed mTOR signaling dysregulation in IUGR fetal kidneys. Before HFCS, gene expression analysis indicated that dysregulation persists postnatally in IUGR females. IUGR male offspring response to HFCS showed uncoordinated signaling pathway responses suggestive of proximal tubule injury. To our knowledge, this is the first study comparing CON and IUGR postnatal juvenile NHP and the impact of fetal and postnatal life caloric mismatch. Perinatal history needs to be taken into account when assessing renal disease risk.

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Bishop, A. C., Spradling-Reeves, K. D., Shade, R., Lange, K. J., Birnbaum, S., Favela, K., Dick, E. J., Nijland, M. J., Li, C., Nathanielsz, P. W., Cox, L. A.. 2020-12-02. Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates. https://doi.org/10.1101/2020.12.01.406355

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