Postnatal persistence of nonhuman primate sex-dependent renal structural and molecular changes programmed by intrauterine growth restriction

Abstract

Background: Poor nutrition during fetal development programs postnatal kidney function. Understanding postnatal consequences in nonhuman primates (NHP) is important for translation to our understanding the impact on human kidney function and disease risk. We hypothesized that intrauterine growth restriction (IUGR) in NHP persists postnatally, with potential molecular mechanisms revealed by Western-type diet challenge.

Methods: IUGR juvenile baboons were fed a 7-week Western diet, with kidney biopsies, blood, and urine collected before and after challenge. Transcriptomics and metabolomics were used to analyze biosamples.

Results: Pre-challenge IUGR kidney transcriptome and urine metabolome differed from controls. Post-challenge, sex and diet-specific responses in urine metabolite and renal signaling pathways were observed. Dysregulated mTOR signaling persisted postnatally in female pre-challenge. Post-challenge IUGR male response showed uncoordinated signaling suggesting proximal tubule injury.

Conclusion: Fetal undernutrition impacts juvenile offspring kidneys at the molecular level suggesting early-onset blood pressure dysregulation.

Keywords: IUGR; caloric mismatch; kidney; nonhuman primate.

FIGURE 1

Principal component analysis (PCA) of sex differences within the renal transcriptome. PCA reveals sex differences in renal transcripts on both chow diet (A) and HFCS diet (B). Blue denotes females; red denotes males

FIGURE 2

Principal component analysis (PCA) of sex differences within the urine metabolome. PCA reveals sex differences in urine metabolites signature on chow diet (A) and HFCS diet (B). Blue denotes females; red denotes males

FIGURE 3

Renal transcriptome comparison of IUGR vs CON females maintained on chow diet. Merged HIF1A, HOXA10, and RB1 inhibitory regulatory networks in IUGR F vs CON F fed the chow diet. Red fill denotes up‐regulated genes, green down‐regulated, blue predicted down‐regulated, orange predicted up‐regulated, gray were not different, and white fill were not detected. Lines with arrows denote activation; lines ending in perpendicular line denote inhibition

FIGURE 4

Renal transcriptome comparison of IUGR vs CON males maintained on chow diet. Role of BRCA1 in the DNA damage response signaling pathway in IUGR males compared with CON males fed the chow diet. Red fill denotes up‐regulated genes in IUGR males compared with CON males, gray fill indicates genes that were not different, and white fill was not detected. Lines with arrows denote activation

FIGURE 5

Renal transcriptome comparison of CON females fed the HFCS diet compared with chow diet. Activated (A) and inhibited (B) regulatory networks in CON females fed the HFCS diet versus chow diet. Red fill denotes up‐regulated genes, green down‐regulated, blue predicted down‐regulated, orange predicted up‐regulated, gray were not different, and white fill were not detected. Lines with arrows denote activation; lines ending in perpendicular line denote inhibition

FIGURE 6

Renal transcriptome comparison of IUGR females fed the HFCS diet compared with chow diet. (A) Down regulation of mTOR signaling in renal transcriptome of IUGR females fed the HFCS diet compared with chow diet. Green fill denotes down‐regulated genes in IUGR females compared with CON females, gray fill indicates genes that were not different, and white fill were not detected. Lines with arrows denote activation; lines ending in perpendicular line denote inhibition. (B) Activation of SMARCA4 regulatory network in renal transcriptome of IUGR females fed the HFCS diet compared with chow diet. Red fill denotes up‐regulated genes, green down‐regulated, and orange predicted up‐regulated

FIGURE 7

Renal transcriptome comparison of CON males fed the HFCS diet compared with chow diet. Merged CREB1, AR, and SRF activated regulatory networks in CON males fed the HFCS diet versus chow diet. Red fill denotes up‐regulated genes, green down‐regulated, and orange predicted up‐regulated. Lines with arrows denote activation; lines ending in perpendicular line denote inhibition

FIGURE 8

Renal transcriptome comparison of IUGR males fed the HFCS diet compared with chow diet. Merged PARP1 and POU4F1 inhibited regulatory networks in IUGR males fed the HFCS diet versus chow diet. Red fill denotes up‐regulated genes, green down‐regulated, and blue predicted down‐regulated. Lines with arrows denote activation; lines ending in perpendicular line denote inhibition