Abstract: SA-PO550

Maintenance of Mature Collecting Duct Principal Cells Is Dependent on Notch Signaling

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

  • Mukherjee, Malini, Sanford Research , Sioux Falls, South Dakota, United States
  • DeRiso, Jennifer, Sanford Research , Sioux Falls, South Dakota, United States
  • Surendran, Kameswaran, Sanford Research , Sioux Falls, South Dakota, United States
Background

During kidney development Notch signaling endows the collecting ducts with proper urine concentrating capacity by ensuring that a sufficient number of collecting duct cells differentiate into mature principal cells instead of selecting intercalated cell fates. Based on the continued expression of Notch ligands in intercalated cells adjacent to mature principal cells we tested the hypothesis that Notch signaling is required for the maintenance of the mature principal cell state.

Methods

Three different mouse models were generated to study the role of Notch signaling in the mature mouse collecting ducts: (i) ectopic expression of dominant-negative mastermind like-1 (dnMaml), a known inhibitor of Notch/RBPJ-mediated transcriptional activation, in mature mouse kidney epithelial cells, (ii) conditional genetic inactivation of Notch1 and Notch2 in the mature kidney epithelial cells of mice starting at three weeks of age, and (iii) conditional genetic inactivation of the down-stream Notch-signaling target Hes1 in the renal epithelium starting at three weeks of age.

Results

Inhibition of Notch signaling in the adult mouse kidneys resulted in a significantly decreased urine concentrating capacity when compared with that of control littermates in all three mouse models. Induction of dnMaml expression in the renal epithelia of three week old mice for three days reduced expression of Nrarp, a gene known to be transcriptionally regulated by Notch signaling, along with principal cell specific genes such as Aqp2 and Avpr2, while expression of intercalated cell specific genes, Foxi1 and Slc4a9, were increased. Genetic inactivation of Notch1 and Notch2 or Hes1 in the mature epithelial cells of the mouse kidneys resulted in reduced number of principal cells and increased number of intercalated-like cells as determined by immunohistochemistry.

Conclusion

Notch signaling is required for maintaining mature principal cells in a functional state by ensuring continued expression of critical principal cell specific genes, and repressing essential intercalated cell specific genes. Lineage tracing of principal cells during kidney development revealed that inhibition of Notch signaling causes principal into intercalated-like cell transdifferentiation. Similarly, Notch signaling appears to prevent transdifferentiation of mature principal cells in the adult mouse kidneys.

Funding

  • NIDDK Support