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Abstract: SA-OR014

Arginase 1 Knockout Macrophages Fail to Promote Epithelial Proliferation and Impair Kidney Repair after AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Marlier, Arnaud, Yale University School of Medicine, New Haven, Connecticut, United States
  • Tharakan, Serena Margaret, Yale University School of Medicine, New Haven, Connecticut, United States
  • Nielsen, Søren, Aalborg University, Aalborg, Denmark
  • Cantley, Lloyd G., Yale University School of Medicine, New Haven, Connecticut, United States
Background

Renal ischemic injury induces epithelial cell death which leads to an innate immune response that includes initial proinflammatory macrophage activation that promotes additional epithelial injury followed by alternative activation that is required for kidney repair. Alternative activation is marked by the expression of several genes including arginase 1 (Arg1), mannose receptor (Mrc1) and macrophage scavenger receptor (Msr1), but the actual function of the protein products of these genes in the injured kidney is not known. This work addresses the role of Arg1 expression by reparative macrophages in kidney repair.

Methods

AKI model: Unilateral renal ischemia reperfusion with contralateral nephrectomy in Arg1f/f;LysMCre/+ (Arg1ko: knock-out of Arg1 in macrophages) and Arg1+/+;LysMCre/+ (Arg1con: control) mice. RNA was isolated either from whole kidney or from flow sorted macrophages (CD45+F4/80+). Gene expression profiling by qPCR. Immunohistology performed on paraffin embedded kidney sections.

Results

Arg1ko (n=8) and Arg1Ctrl (n=9) mice were therefore subjected to 27 minutes of unilateral IR with contralateral nephrectomy. The initial rise in creatinine on day 1 was equivalent in the 2 groups (1.55±0.05 and 1.61±0.05 mg/dl, p=ns). 85% of the control mice survived to day 7 after IR, whereas only 37% Arg1ko mice survived until day 7, with mortality observed on day 3. Renal macrophage expression of Arg1 on day 7 after IR is 0.755±0.484 in control mice but only 0.020±0.012 in Arg1ko mice (dCt relative to Hprt1, p=0.04). Quantification of F4/80+ cells in the kidney on day 3 revealed no difference in macrophage numbers between control and Arg1ko mice (298±83 vs. 315±17 F4/80+ cells/mm2, p=ns), whereas tubular cell proliferation as determined by Ki67 positivity was significantly reduced in Arg1ko kidneys (343±86 vs. 110±33 Ki67+ cells/mm2, p=0.03). Finally, morphometric analysis of day 7 kidney sections showed a pronounced loss of healthy tubular mass in Arg1ko kidneys compared to control kidneys (normal tubule/ section: 34.2%±2.7 vs. 44.7%±0.5, p=0.004).

Conclusion

These results indicate that the upregulation of macrophage Arg1 expression facilitates tubular regeneration by promoting epithelial cell proliferation and limiting nephron loss at the site of injury.

Funding

  • Other NIH Support