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Abstract: FR-PO402

In Utero Exposure to Maternal Diabetes Reprograms Nephron Formation and Predisposes to Hypertension and CKD

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Malta C.S Santos, Debora, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Chiba, Takuto, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Bruder do Nascimento, Ariane, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Clugston, Andrew Scott, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Tayeb, Maliha, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Bodnar, Andrew J., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Kostka, Dennis, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Bruder do Nascimento, Thiago, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Ho, Jacqueline, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background

The prevalence of diabetes has markedly increased among pregnant women worldwide and infants who are exposed to maternal diabetes in utero are at increased risk of congenital anomalies of the kidney and urinary tract (CAKUT). These anomalies can result in a reduction in the number of nephrons formed during kidney development, which is linked to hypertension and chronic kidney disease (CKD). However, it remains unclear how exposure to maternal diabetes in utero reprograms the developing kidney, predisposing to hypertension and CKD later in life.

Methods

We used the Ins2+/C96Y mouse as a genetic model of maternal type 1 diabetes. Diabetic Ins2+/C96Y females were bred with wildtype C57BL/6J males, and the wildtype offspring (DM_Exp) were compared to wildtype offspring from C57BL/6J dams (=Control). Nephron numbers were estimated using the gold-standard physical dissector/fractionator method. scRNA-seq was performed on postnatal day 2 (P2) kidneys. Renal ischemia reperfusion injury was performed in male 3-month-old mice, and renal function was examined by BUN and sCr levels. Radio-telemetry was utilized to measure continuous blood pressure in male 6-month-old mice.

Results

Adult DM_Exp mice exhibited a nephron deficit of approximately 20% with no associated growth restriction. The expression of the nephron progenitor markers, Six2 and Cited1, was increased in DM_Exp kidneys, while the number of developing nephrons was significantly reduced at postnatal day 2 (P2). This was accompanied by reduced levels of the miR-200 family and increased expression of their target genes, Zeb1/2. Moreover, increased DNMT3a expression was observed in DM_Exp kidneys. scRNA-seq indicated that the majority of significantly differentially expressed genes occur in the distal tubules and many of them encode solute transporters. Finally, adult DM_Exp mice exhibited increased susceptibility to acute kidney injury and salt-sensitive hypertension.

Conclusion

Together, these data suggest that the diabetic intrauterine environment reprograms nephron formation and function via epigenetic mechanisms, predisposing to hypertension and CKD later in life.

Funding

  • NIDDK Support