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Abstract: FR-OR030

Macula Densa Cells Orchestrate Podocyte Neogenesis

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gyarmati, Georgina, University of Southern California, Los Angeles, California, United States
  • Shroff, Urvi nikhil, University of Southern California, Los Angeles, California, United States
  • Riquier-brison, Anne, University of Southern California, Los Angeles, California, United States
  • Schiessl, Ina M., University of Southern California, Los Angeles, California, United States
  • Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States
Background

The recruitment of new podocytes from precursor cells including parietal epithelial cells (PECs) and cells of the renin lineage (CoRL) in response to glomerular injury has been established, however the mechanism remains elusive. Here we tested the hypothesis that macula densa (MD) cells localized at the glomerular entrance are master organizers of glomerular remodeling, and can be stimulated to recruit new podocytes in the adult kidney.

Methods

Intravital multiphoton imaging (MPM) in genetic mouse models was performed to track the fate and migration pattern of mesenchymal and endothelial precursor cells. RNA seq and gene profiling was used to establish and analyze the gene profile of MD cells under control and stimulating conditions. Immunohistochemistry for podocyte, mesenchymal, and endothelial precursor cell markers p57, WT-1, and CD34 were performed in kidney sections of control WT mice and in a new genetic model of inducible MD-specific Wnt gain-of-function (gof).

Results

MPM provided “smoking gun” direct visual evidence for the migration of single CoRL from the PEC layer to the glomerular tuft (sometimes within 15 s) in the intact mouse kidney. The newly established, exclusively MD-specific secretome includes several angiogenic, patterning, growth factor, and extracellular matrix remodeling peptides including Pappa2, Ccn1, Cxcl14, Wnt10a, Sema3c, Bmp3, Egfl6, Fgf9, Vegfd, Pdgfc, Frem1, etc. In MD-Wnt(gof) mice, glomerular size and podocyte number increased from control 17±3 to 24±3 per unit glomerular volume within 5 weeks. MD-Wnt gof also developed a WT-1+ cell niche at the MD base/extraglomerular mesangium transitioning into the Bowman’s capsule, and a CD34+ endothelial precursor cell niche at the glomerular vascular pole. Treatment of Ren1d-Confetti mice with GSK3b inhibitors for only 5 days caused a 3-fold increase in the density of CoRL at the glomerular vascular pole and in PEC layer.

Conclusion

These results suggest that MD cells are central players in the physiological remodeling of the glomerulus via Wnt signaling and secreted paracrine factors, that act on the mesenchymal-to-epithelial transition of glomerular precursor cells to become new podocytes. MD cells also stimulate angiogenesis simultaneously. This new mechanism protects from glomerular injury when augmented, and may be developed further to specifically treat glomerular diseases.

Funding

  • NIDDK Support