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Kidney Week

Abstract: FR-PO963

Macrophage-Specific Deletion of Cytosolic Nucleotide Sensors Ameliorate Kidney Fibrosis and Inflammation

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Sanchez-Navarro, Andrea, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Dhillon, Poonam, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

The cytosolic DNA sensors, such as cGAS-STING are part of the innate immune system providing the first line of defense against cytosolic viruses and prime and activate the adaptive immune system. Our previous studies suggested that global deletion or pharmacological inhibition of STING ameliorates fibrosis. Here we analyzed the cell-type specific role of cGAS-STING.

Methods

We generated a macrophage-specific cGAS and STING knockout mice by crossing the cGASflox and STINGflox mice with Lyz2-Cre animals. We induced kidney injury by unilateral ureteral obstruction (UUO) or cisplatin injection. The degree of kidney injury was estimated based on blood biomarkers, BUN, creatinine, renal histology and kidney gene and protein expression changes by QRT-PCR and Western blots, respectively. We studied macrophages (RAW264.7) cells in vitro using cGAS and STING siRNA.

Results

Mice with macrophage-specific deletion of cGAS or STING was healthy at baseline. Wild type cisplatin injected animals had increased expression of kidney injury markers (Ngal, Kim1), which was lower in cGAS and STING knock-out mice. UUO mice showed higher expression of fibrosis associated markers, which again was ameliorated in macrophage specific cGAS and STING knock-out mice. Markers of inflammation Mcp1, Interleukin-6 (Il-6) and Interleukin-1β (Il-1β) was markedly lower in both models. Expression of Il-6 and Il-1β was lower peritoneal macrophages isolated from Lyz2Cre-STING mice. Moreover, silencing STING in cultured mice macrophages cell line ameliorated M1 pro-inflammatory polarization and enhanced M2 anti-inflammatory polarization.

Conclusion

cGAS-STING mediated macrophage polarization play an important role in the inflammatory and profibrotic response in kidney injury and fibrosis.

Funding

  • NIDDK Support