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Abstract: TH-OR080

Novel Neuroendocrine Features of Macula Densa Cells Suggest Their Chief Role in Glomerular Tissue Remodeling

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gyarmati, Georgina, University of Southern California, Los Angeles, CA 90033, California, United States
  • Riquier-brison, Anne, University of Southern California, Los Angeles, CA 90033, California, United States
  • Shroff, Urvi Nikhil, University of Southern California, Los Angeles, CA 90033, California, United States
  • Peti-Peterdi, Janos, University of Southern California, Los Angeles, CA 90033, California, United States
Background

Macula densa (MD) cells are strategically positioned at the glomerular entrance and traditionally known to regulate renal hemodynamics and renin release. The present study aimed to explore the emerging new neuron-like and secretory function of MD cells and their role in glomerular angiogenesis and tissue maintenance.

Methods

A newly developed MD cell research toolbox was applied including MD-GFP, MD-GCaMP5, Cdh5-Confetti mouse models for tracking MD and endothelial genetic cell fate and [Ca2+]i dynamics with intravital multiphoton imaging (MPM), freshly isolated single live MD cells, the newly established immortalized mouse MD cell line MDGeo, and MD gene profiling.

Results

Mouse MD cell gene profile suggested axon guidance and growth as key MD cell functions, and high expression of secreted tissue remodeling and angiogenic factors Ccn1, Nov, Cxcl14, Pappa2, Sema3c. MD-GFP mice enabled the visualization of single MD cells in high detail and confirmed the presence of a dense network of long (up to 100 um) basal cell processes arborizing into the glomerular mesangium and vasculature, with highly dynamic features including rapid and extensive vesicular transport and outgrowth. MDGeo cells showed high expression of nerve growth factor receptor (NGFR) and the regulation of nNOS and COX2 expression by NGF. In vivo MPM of MD cell [Ca2+]i revealed that unlike in other renal epithelia, MD cells show robust (5-fold compared to baseline), rapid, and propagating calcium transients (2-4 s spikes) that were due to several neuron-specific calcium entry, mobilization, and extrusion pathways. MDGeo cells but not control M1 cells implanted under the renal capsule of Cdh5-Confetti mice induced within 4 days robust endothelial sprouting, neovascularization (angiogenesis). The radial pattern of new vessel growth towards the implanted MD cells' epicenter was formed by clonally expanding local endothelial precursor cells and contained circulating red blood cells.

Conclusion

The newly identified MD cell morphological and functional features suggest that the MD plaque is a single nephron-level ganglion of individual neuron-like MD cells that play chief sensory, effector, and neuroendocrine functions in the kidney. Novel MD-derived secreted angiogenic factors may contribute to glomerular tissue maintenance and repair after injury.

Funding

  • NIDDK Support