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Abstract: TH-PO802

High Activity of Tissue Remodeling Cell Signaling Cascades in the Macula Densa

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Shroff, Urvi nikhil, University of Southern California, Los Angeles, California, United States
  • Gyarmati, Georgina, University of Southern California, Los Angeles, California, United States
  • Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States
Background

The macula densa (MD), a plaque of 15-20 specialized cells, sits at the vascular pole of the glomerulus and plays a traditional role in maintaining renal hemodynamics and the renin-angiotensin system. However, the new tissue remodeling function of MD cells is emerging. The present study aimed to examine the activity and role of major cell signaling pathways in MD cells, and to test if augmenting these pathways specifically in MD cells would alter renal tissue remodeling.

Methods

RNA seq and gene profiling was used to establish and analyze the gene profile of mouse MD cells under control and stimulating low dietary salt conditions. To confirm MD specificity of top gene candidates, immunohistochemistry (IHC) was performed on mouse and human kidney sections for Wnt/β-catenin, mTOR, PI3K, and MAPK signaling pathways that are known to regulate cell biology and tissue remodeling. To test for cell proliferation and rate of protein synthesis, EdU staining and a O-propargyl-puromycin incorporation-based assay were performed, respectively, in kidney sections of control WT mice and in a new genetic model of inducible MD-specific Wnt gain-of-function (gof).

Results

Combined gene profiling and IHC identified the highest activity of Wnt, mTOR, PI3K, and MAPK signaling in MD cells in the mouse and human kidney cortex. A TCF/Lef:H2B-GFP Wnt signaling reporter mouse model and activated β-catenin IHC showed the strongest labeling in MD cells. In MD-Wnt(gof) mice after 5 weeks of induction, a robust increase in MD cell proliferation, nucleus-to-cell volume ratio, and protein synthesis were found compared to WT control. MD-Wnt(gof) mice also featured enlarged glomeruli, increased PDGFRβ+ mesangial expansion and angiogenesis. Treatment with lithium (GSK3β inhibitor for Wnt stimulation) for 2 weeks had similar effects on MD cell morphology, cell biology, glomerular size and cell composition.

Conclusion

In summary, the renal cell type with the strongest Wnt, mTOR, PI3K, and MAPK activity is the MD, which is a chief sensor and effector of the local tissue environment. Wnt signaling is an important regulator of MD morphology, cell biology, and new function in tissue remodeling, which can be augmented in new developing regenerative therapeutic strategies.

Funding

  • NIDDK Support