Abstract: SA-PO558

Intrauterine Growth Restriction (IUGR) by Maternal Protein Undernutrition Disrupts the Transcriptional Networks of Energy Metabolism in Nephron Progenitors

Session Information

  • Developmental Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

  • 401 Developmental Biology

Authors

  • Edgington-Giordano, Francesca, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Liu, Hongbing, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Hilliard, Sylvia, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Liu, Jiao, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Li, Yuwen, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Song, Renfang, Tulane University School of Medicine, New Orleans, Louisiana, United States
  • Saifudeen, Zubaida R., Tulane University School of Medicine, New Orleans, Louisiana, United States
  • El-Dahr, Samir S., Tulane University School of Medicine, New Orleans, Louisiana, United States
Background

Fetal IUGR from maternal undernutrition is linked to reduced nephron endowment, resulting in suboptimal renal function and a predisposition towards hypertension and chronic kidney disease. Using an established protein-deficiency mouse model of IUGR, we examined the impact of maternal undernutrition on nephron progenitor cell (NPC) maintenance and gene expression.

Methods

CD1 mice were fed isocaloric low-protein (6%) or control (20% protein) diets 3 weeks prior to timed mating. Kidneys were harvested at P0 to assess NPC pool size (Six2, NCAM) and differentiating nephrons (NCAM, Lhx1, WT1) by IF. RNA-Seq was performed on RNA isolated from native NPC of P0 kidneys (n=3), and data analyzed by IPA and GO-Panther. Bonferroni correction was applied.

Results

Significantly reduced (p<0.0001) P0 body and kidney weight were observed. However, kidney/body weight ratios are not significantly changed in 6% vs 20% pups. 6% pups show diminished nephrogenic zone, a smaller Six2+ NPC pool and nascent nephron deficit (p<0.0001, n=4). Increased immunostaining for p53, phospho-p38 and phospho-ATF2 indicate activation of fetal cellular response to maternal nutritional stress. Mitosis marker phospho-histone H3 staining in the NPC is decreased. RNASeq data show 1,694 upregulated and 2,114 down-regulated genes (1.5-fold cut-off). Top gene enrichment in Biological Processes include RNA splicing/metabolism, cellular metabolic process and cellular component biogenesis. Highest enrichment of genes in Cellular Component was observed for ribonucleoprotein complex and mitochondrion. Energy metabolism categories (EIF2 signaling, Glycolysis, mTOR, eIF4/p70S6K) top the canonical pathways. Expression of renewing NPC markers Cited1, Six2 and Meox are unchanged. Differentiation/induction marker Wnt4 expression was unchanged, however Lhx1 and Jag1 expression decreased more than 2-fold. ISH show decrease in Bmp7, Wnt11 and Wnt9b mRNA.

Conclusion

Pups from undernourished moms demonstrate decreased NPC pool and nascent nephrons. Cellular processes and metabolism are the profoundly altered at the transcriptional level in the NPC. For the long-term, this mouse is an excellent model to analyze how maternal undernutrition impacts offspring kidney development and function.

Funding

  • NIDDK Support