Kidney Week

Abstract: PO2507

Targeting ARG1+ Macrophages Slows the Progression of AKI to CKD

Session Information

• CKD: Metabolism, Epigenetics, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Author

• Zeng, Rui, Huazhong University of Science and Technology Tongji Medical College, Wuhan, Hubei, China

Rui Zeng, MD, PhD

Background

Recently, ARG1⁺ myeloid cells were defined as a new subgroup that express a large number of pro-inflammatory and pro-fibrotic genes. However, its function and clinical application in kidney disease has not yet been identified.

Methods

We clarified the source of ARG1⁺ macrophages via the bone marrow transplantation and the parabiosis, and constructed macrophage-specific ARG1 knockout mice (ARG1^fl/fl; CX3CR1^creERT2) and CX3CR1^CreERT2-DTR mice. Kidney samples were analyzed through 10X single-cell sequencing technology. The arginase inhibitor nor-NOHA and RNAi lentiviral vector of ARG1 were applied to ischemia-induced kidney injury.

Results

Most of the intra-renal ARG1⁺ macrophages were from bone marrow. Knocking down ARG1 in macrophages alleviated ischemia-induced AKI and the subsequent chronic fibrosis, and reduced the infiltration of macrophages in the kidney, while depletion of CX3CR1⁺ cells aggravated ischemia-induced renal injury. GSEA analysis found that the function of ARG1⁺ macrophages significantly enriched in the regulation of the release of inflammatory factors, activation of immune inflammatory response, and secretion of extracellular matrix. More biological macrophage ligand–mesenchymal receptor pairs expressed in ARG1⁺ macrophages between mesenchymal cells, compared to ARG1^– macrophages. Inhibiting ARG1 activity alleviated the proliferation of ARG1⁺ macrophages and reduced ischemia-induced renal fibrosis. The application of RNAi lentiviral vector of ARG1 via the tail vein injection alleviated the renal fibrosis, reduced ARG1 expression and macrophage infiltration.

Conclusion

ARG1⁺ macrophages accelerated the development of AKI to CKD by promoting inflammation response, activating fibroblasts and secreting extracellular matrix proteins. Inhibiting the activity or expression of ARG1 in macrophages alleviate IR-induced renal fibrosis.