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Abstract: FR-PO752

In Utero Exposure to Maternal Diabetes Impairs Nephron Progenitor Differentiation

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Malta C.S Santos, Debora, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hemker, Shelby L., University of Pittsburgh - Rangos Research Center, Pittsburgh, Pennsylvania, United States
  • Bodnar, Andrew J., University of PIttsburgh, Pittsburgh, Pennsylvania, United States
  • Ortiz, Daniella, University Michigan Medical School, Ann Arbor, Michigan, United States
  • Oladipupo, Favour O., University of Pittsburgh School of Medicine, North Bethesda, Maryland, United States
  • Mukherjee, Elina, University of Pittsburgh - Rangos Research Center, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Ho, Jacqueline, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

The incidence of diabetes mellitus has significantly increased among women of childbearing age worldwide and infants exposed to maternal diabetes in utero are at increased risk of congenital renal anomalies. In this study, we utilized a genetic model of maternal type 1 diabetes, the Akita (Ins2+/C96Y) mice, to evaluate its effect on kidney development.

Methods

Diabetic Ins2+/C96Y females were bred with wildtype C57BL/6J males and, wildtype offspring exposed to maternal diabetes in utero (DM_Exp) were assessed. Wildtype offspring from C57BL/6J dams were used as controls. Kidneys were collected at different postnatal days (P0, P2 and P34). Nephron numbers were estimated using the gold-standard physical dissector/fractionator method. The expression of nephron progenitor and developing nephron markers was analyzed by qPCR, immunohistochemistry and/or Western blot.

Results

Adult DM_Exp mice (P34) exhibited a nephron deficit of approximately 20% with no association with growth restriction. At P2, the rate of apoptosis and cell proliferation in nephron progenitors was unchanged. However, the expression of the nephron progenitor markers, Six2 and Cited1, was increased in DM_Exp kidneys. In association with this, there was a significant reduction in the total number of early developing nephrons (i.e., renal vesicle, comma- and S-shaped body structures) in DM_Exp kidneys compared to control kidneys. This was associated with reduced expression of the intracellular domain of Notch 1 (NICD) and the canonical Wnt target lymphoid enhancer binding factor 1 (Lef1).

Conclusion

Together, these data suggest that the diabetic intrauterine environment impairs the differentiation of nephron progenitors into nephrons, which may be mediated by diminished Wnt/β-catenin and Notch signaling pathways.