IL-34/PTP-ζ Axis on Macrophages Promotes Renal Fibrosis in Mice with Unilateral Ureteral Obstruction

Background: Previously, we have demonstrated the intrarenal upregulation of protein-tyrosine phosphatase ζ receptor (PTP-ζ), the second receptor for interleukin (IL)-34 for macrophages (Mø) proliferation, in mice with unilateral ureteral obstruction (UUO). However, the specific site of PTP-ζ expression in UUO kidneys and the role of IL-34/PTP-ζ axis in renal fibrosis remain elusive. Methods: 10-week-old male wild-type (WT) C57BL/6 (B6) mice (n = 14) and age-matched PTP-ζ knockout (KO) B6 mice (n = 16) were induced UUO. All mice were sacrificed on day 14. In vitro, mouse bone marrow-derived macrophages (BMMø) were isolated for analysis. Results: Compared to sham ope mice, the UUO kidneys of WT mice exhibited severe renal fibrosis with significant intrarenal expressions of IL-34 and PTP-ζ. In the KO mice, the sirius-red+ area in UUO kidneys, was significantly reduced compared to WT mice (Fig A, B), despite comparable intrarenal IL-34 expressions. The intrarenal mRNA levels of TGF-β were lower in KO mice. IF analysis revealed that KO mice showed significantly fewer F4/80+ Mø and α-SMA+ myofibroblasts in UUO kidneys, along with lower levels of intrarenal transcripts for Chil3 and Timp-1. FACS analysis showed that the ratio of CD11c-CD206+ cells within intrarenal CD11b+F4/80+ Mø population was higher in KO mice. In vitro, western blotting confirmed PTP-ζ expressions in BMMøs from WT mice after TGF-β (5 ng/mL) stimulation (Fig C). Stimulation with TGF-β and recombinant IL (rIL)-4 (20 ng/mL) significantly increased Arginase 1 transcripts in WT-BMMøs, with further amplification upon treatment with rIL-34 (5 ng/mL). In contrast, rIL-34 treatment did not enhance Arginase 1 mRNA levels in KO-BMMøs mice after TGF-β and rIL-4 stimulation. Conclusion: IL-34 binding to PTP-ζ on Mø proliferate M2-like Mø in UUO kidneys, promoting renal fibrosis by enhancing profibrotic response and accumulating myofibroblasts. Thus, IL-34/PTP-ζ axis on Mø might represent a therapeutic target for renal fibrosis.