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Kidney Week

Abstract: SA-PO083

Myofibroblast-Macrophage Cross-Talk Supports Proliferative Tubule Repair after Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bharathan, Bhavya, Yale University School of Medicine, New Haven, Connecticut, United States
  • Xu, Leyuan, Yale University School of Medicine, New Haven, Connecticut, United States
  • Guo, Jiankan, Yale University School of Medicine, New Haven, Connecticut, United States
  • Cantley, Lloyd G., Yale University School of Medicine, New Haven, Connecticut, United States
Background

After ischemia-reperfusion injury (IRI), macrophages expressing arginase 1 (Arg1) exclusively localize to the outer medulla adjacent to injured and dying S3 proximal tubule cells. Genetic deletion of macrophage Arg1 leads to less tubular proliferation and decreased mouse survival after IRI. Arg1 is known to be required for protein translation, and we speculate that upregulation of Arg1 leads to macrophage secretion of unidentified factor(s) that are required for downstream tubular cell proliferation.

Methods

Unilateral IRI with contralateral nephrectomy (IRI/CL-NX) was used to induce ischemic kidney injury in mice. Cultured macrophages were induced to express Arg1 by co-culture with renal tubular cells + GM-CSF. We performed bulk RNA sequencing and quantitative PCR (qPCR) of primary cultured renal cells and single cell RNA sequencing of mouse kidneys 3 days after IRI or sham to identify relevant growth factors and cell types after IRI. PDGFRβ± cells were isolated from injured and control kidneys using Magnetic-Activated Cell Sorting, and RNA was isolated to analyze relevant growth factors by qPCR.

Results

scRNAseq from day 3 injured kidneys demonstrated that Insulin-like Growth Factor-1 (Igf1) is upregulated in myofibroblasts (PDGFRβ+ cells), and Igf1 Receptor (Igf1R) is upregulated on proximal tubule cells. Conditioned medium from Arg1 expressing macrophages induced an 8.95-fold increase in expression of Igf1 in cultured PCRC (containing a mix of ~94% tubular cells and ~5% PDGFRβ+ myofibroblasts). Isolation of PDGFRβ+ cells from the kidney on day 2 after IRI revealed a 14.83±0.14-fold increase in Igf1 in these myofibroblast-enriched cells as compared to PDGFRβ- cells (p<0.0001), with a 7.51±0.14 fold increase compared to PDGFRβ+ cells from uninjured kidneys (p<0.0002)

Conclusion

Arg1-expressing macrophages secrete a yet unidentified factor(s) that can induce Igf1 expression by primary cultured renal cells, likely myofibroblasts, with concomitant upregulation of Igf1R on tubular cells. We hypothesize that this macrophage-myofibroblast crosstalk underlies Igf1-induced proliferative tubule repair by surviving proximal tubule cells.

Funding

  • NIDDK Support