Kidney Week

Abstract: SA-PO309

Kidney-Resident Macrophages (KRM) Upregulate Pro-Angiogenic Response in Chronic Ischemic Kidney Injury

Session Information

• Mechanisms Associated with Kidney Fibrosis - II
  November 04, 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

• Puranik, Amrutesh, Mayo Clinic, Rochester, Minnesota, United States

Amrutesh Puranik,

• Leaf, Irina Alexandra, Biogen, Cambridge, Massachusetts, United States

Irina Alexandra Leaf,

• Saad, Ahmed, Mayo Clinic, Rochester, Minnesota, United States

Ahmed Saad,

• Grande, Joseph P., Mayo Clinic, Rochester, Minnesota, United States

Joseph P. Grande,

• Textor, Stephen C., Mayo Clinic, Rochester, Minnesota, United States

Stephen C. Textor,

• Lerman, Amir, Mayo Clinic, Rochester, Minnesota, United States

Amir Lerman,

• Duffield, Jeremy Stuart, Vertex Pharmaceuticals, Boston, Massachusetts, United States

Jeremy Stuart Duffield,

• Lerman, Lilach O., Mayo Clinic, Rochester, Minnesota, United States

Lilach O. Lerman,

Background

Macrophages (Mφ) play important roles in regulating progression & resolution of renal injury in renal artery stenosis (RAS). We have recently found that murine kidney Mφ expressing CD64⁺F4/80⁺FCRIV⁺CD11b^intCD11c^int are anti-fibrotic and reparative. We hypothesized that these are KRM & expand in mouse and human renal ischemic disease

Methods

Using CX3CR1^creER:Rosa26^tdTomato mice we fate-mapped the KRM and studied their kinetics in RAS. To dissect molecular mechanisms potentially underlying their protective properties in RAS, we compared KRM transcriptional profiles to non-KRM Mφ by RNA Sequencing (Fig A). Furthermore, we identified CD11b^intCD11c^intCD68⁺ KRM in human kidney biopsies of normal and RAS patient kidneys and correlated their number with kidney function (Fig B).

Results

Fate-mapping studies identified CD64⁺F4/80⁺CD11b^intCD11c^int as KRM. BrdU labeling show KRM expand in RAS. KRM showed a more robust response to RAS compared to Sham KRM and non-KRM Mφ (Fig A). RAS KRM were transcriptionally heterogeneous, containing both pro- and anti-inflammatory pathways. Angiogenic Pathway was the greatest functionally enriched in RAS-KRM. Further, while both KRM and non-KRM upregulated immune pathways, only KRM downregulated immune genes including Irf5, a molecular switch to pro-inflammatory states. Finally, KRM number significantly (Fig C) increased in human stenotic kidney biopsies compared to normal and correlated with better kidney function and lower fibrosis (Fig D).

Conclusion

Thus, murine CD64⁺F4/80⁺FCRIV⁺CD11b^intCD11c^int Mφ are KRM, and can also be identified in human kidneys. KRM show a more robust response to chronic ischemic kidney injury compared to non-KRM Mφ, upregulating a pro-angiogenic and reparative gene profile. These observations may have important prognostic and therapeutic implications in chronic kidney injury.

Funding

• NIDDK Support