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Abstract: SA-OR47

Proliferation Control of Interstitial Cells in the Neonatal Kidney

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Author

  • Oxburgh, Leif, The Rogosin Institute, New York, New York, United States
Background

Expansion of interstitial cells in the adult kidney is a hallmark of chronic disease, whereas their proliferation during fetal development is necessary for organ formation. An intriguing difference between adult and neonatal kidneys is that the neonatal kidney has the capacity to control interstitial cell proliferation when the target number has been reached. In this study, we define the consequences of inactivating the TGFb/Smad response on proliferation control of the renal interstitium in the neonatal mouse.

Methods

Smad4 was inactivated using the Foxd1cre mouse strain, which is specifically expressed in interstitial progenitor cells in the developing kidney. Loss of Smad4 in interstitial cells was confirmed by single cell genotyping and immunostaining. Interstitial cell lines with tamoxifen-inducible loss of Smad4 were generated from primary interstitial cells for molecular interaction studies.

Results

We find that loss of Smad4 leads to over-proliferation of interstitial cells regionally in the kidney medulla. Analysis of signaling pathway markers in tissue showed that activation of Smad3 is deficient, whereas activation of Smad1/5 is largely unaffected, indicating an effect specifically on TGFb signaling. Genetic and molecular interaction studies showed that Smad3/4 participates in the Wnt/b-catenin signaling pathway in interstitial cells, which is responsible for promoting their proliferation. Specifically, Smad4 is required for the expression of the Wnt feedback inhibitor Apcdd1.

Conclusion

Based on these findings, we propose a model for interstitial cell proliferation control in which the Wnt/b-catenin proliferative signal is attenuated by TGFb/Smad signaling to ensure that proliferation ceases when the target number of interstitial cells has been reached in the neonatal medulla.

Model for proliferation control of medullary interstitial cells

Funding

  • NIDDK Support