Kidney Week

Abstract: SA-PO562

Macula Densa mTOR Signaling Regulates Renin Cell and Glomerular Endothelial Remodeling

Session Information

• Glomerular Diseases: Fibrosis, Extracellular Matrix
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Shroff, Urvi Nikhil, University of Southern California, Los Angeles, California, United States

Urvi Nikhil Shroff,

• Riquier-brison, Anne, University of Southern California, Los Angeles, California, United States

Anne Riquier-brison,

• Izuhara, Audrey, University of Southern California, Los Angeles, California, United States

Audrey Izuhara,

• Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States

Janos Peti-Peterdi,

Background

Macula densa (MD) cells are critical regulators of glomerular filtration rate, renal blood flow and renin release via paracrine signaling that involves MD MAP kinases ERK1/2 and p38, and the MD-specific enzymes COX2 and nNOS. The mTOR complex is known to act as a central mediator, integrating the downstream effects of several cell signaling pathways to promote cell growth and protein synthesis. The present study aimed to examine the role of mTOR signaling in regulating MD cell function and its effect on glomerular tissue remodeling.

Methods

An MD-specific genetic mouse model for upregulated mTOR signaling was developed by crossing nNOS Cre mice and mice with a truncated form of TSC2 that upon tamoxifen induction results in mTOR gain-of-function in MD cells (MD-mTOR^gof). Changes in expression of MD molecular players controlling renin release (ERK1/2, COX2, mPGES1, etc.) was quantified in renal cortical tissue homogenates. To test the effect of MD-mTOR signaling on renal tissue remodeling, kidney slices were stained for endothelial cell (Meis2 and CD34) and podocyte markers (WT1) using 3D tissue clearing and histological analysis.

Results

Compared to control WT mice,a significant increase in glomerular diameter, robust expansion of the glomerular mesangium, and hypercellularity at the glomerular vascular pole were observed in MD-mTOR^gofmice. MD-mTOR^gofmice had increased expression of ERK1/2, phospho ERK1/2, COX2 and mPGES1, as well as increased renin expression quantified with immunofluorescence labeling for renin granules and on immunoblots. MD-mTOR^gofmice featured significantly increased number of Meis2⁺glomerular endothelial cells as well as CD34⁺endothelial precursor cells with the highest density close to the MD.

Conclusion

In summary, upregulation of MD-mTOR signaling has robust effects on both the traditional MD cell functions (renin control), and their newly emerging role in long-term glomerular tissue remodeling. Since MD-mTOR signaling significantly affects the glomerular architecture, it may be targeted to develop future therapeutic strategies for endogenous tissue remodeling and repair in glomerular diseases.

Funding

• NIDDK Support