Kidney Week

Abstract: FR-PO338

Perivascular Cell CD73 Modulates Macrophages in the Renal Microenvironment during Progressive Fibrosis

Session Information

• Mechanisms Associated with Kidney Fibrosis - I
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

• Perry, Heather M., University of Virginia, Charlottesville, Virginia, United States

Heather M. Perry,

• Görldt, Nicole, University of Virginia, Charlottesville, Virginia, United States

Nicole Görldt,

• Huang, Liping, University of Virginia, Charlottesville, Virginia, United States

Liping Huang,

• Sung, Sun-sang J., University of Virginia, Charlottesville, Virginia, United States

Sun-sang J. Sung,

• Rosin, Diane L., University of Virginia, Charlottesville, Virginia, United States

Diane L. Rosin,

• Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States

Mark D. Okusa,

Background

Progressive tubulointerstitial fibrosis can occur following an acute kidney insult such as ischemia-reperfusion injury (IRI). Mechanisms underlying these maladaptive repair processes are not well understood. Purinergic signaling by CD73, an enzyme that converts AMP to adenosine on the extracellular surface, via adenosine receptors can suppress inflammation and reduce IRI. As CD73 is expressed on renal perivascular cells (pericytes and/or fibroblasts of the Foxd1+ lineage), we hypothesized that perivascular cell expression of CD73 is necessary to suppress inflammation and prevent fibrosis.

Methods

Foxd1CreCD73^fl/fl and littermate control CD73 ^fl/fl mice were subjected to 20’ unilateral IRI operation and after 14d, plasma was collected to quantify plasma creatinine (PCr). Also, kidneys were prepared for assessment of fibrosis by histology and inflammation and myofibroblast density by immunofluorescence. Kidney fibrosis and macrophage polarization markers were quantified by RT-qPCR. Soluble CD73 or macrophage depletion by liposome clodronate and controls were initiated 2d after IRI and kidney function and fibrosis were assessed at 14d.

Results

PCr levels were elevated in Foxd1CreCD73^fl/fl (n = 10) compared to control mice (n = 9) (0.29 ± 0.07 vs. 1.1 ± 0.20 mg/dl respectively, p < 0.001). Fibrosis and myofibroblast marker expression was increased in kidneys of Foxd1CreCD73^fl/fl mice compared to controls. Kidney macrophages and expression of pro-inflammatory, pro-fibrotic phenotypic markers were also increased in Foxd1CreCD73^fl/fl mice compared to controls. Exogenous CD73 rescued the decline in kidney function and fibrotic phenotype in Foxd1CreCD73^fl/fl mice. As macrophages switch from a pro-inflammatory to a wound healing phenotype on day 2, we sought to address this as a potential mechanism of increased fibrosis in Foxd1CreCD73^fl/fl mice. Macrophage depletion in Foxd1CreCD73^fl/fl mice resulted in protection against kidney dysfunction and fibrosis.

Conclusion

These results demonstrate that perivascular cell CD73 orchestrates the renal inflammatory microenvironment to promote a wound healing response after an acute event resulting in recovery of kidney function and prevention of progressive fibrosis.

Funding

• NIDDK Support