Kidney Week

Abstract: SA-PO1166

Involvement of Protein-Tyrosine Phosphatase ζ Receptor on the Progression of Kidney Fibrosis in Mice with Unilateral Ureteral Obstruction

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Abe, Tetsuya, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Tetsuya Abe, MD

• Wada, Yukihiro, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Yukihiro Wada, MD, PhD

• Satoh, Masashi, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Masashi Satoh, PhD

• Imanishi, Takayuki, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Takayuki Imanishi, PhD

• Otsu, Makoto, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Makoto Otsu, MD, PhD

• Suenaga, Tadahiro, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Tadahiro Suenaga, MD, PhD

• Takeuchi, Yasuo, Kitasato Daigaku Igakubu, Sagamihara, Kanagawa, Japan

Yasuo Takeuchi, MD, PhD

Background

Intrarenal expressions of protein-tyrosine phosphatase ζ receptor (PTP-ζ), the second receptor of interleukin (IL)-34 for macrophage (Mø) proliferation, have been demonstrated in several experimental renal disease models. However, role of PTP-ζ on the progression of renal diseases remains elusive. We investigated the influence of PTP-ζ on renal fibrosis caused by unilateral ureteral obstruction (UUO).

Methods

10-week-old male wild type (WT) C57BL/6 (B6) mice (WT, n = 14) and age-matched male PTP-ζ knockout (KO) B6 mice (KO, n = 16) were induced UUO. Four age-matched male B6 mice received sham operation as control. All mice were sacrificed on day 14. In vitro, mouse Mø cell line (RAW 264.7) or mouse bone marrow-isolated Møs (BMMøs) were stimulated with TGF-β (5 ng/mL), and then treated with or without recombinant IL-34 (r-IL-34) (500 pg/mL) for the effects of PTP-ζ analyses.

Results

Compared to the sham-operated control, the UUO kidneys of WT mice exhibited remarkable intrarenal IL-34 and PTP-ζ expressions. Meanwhile, the KO mice showed deficiency of intrarenal PTP-ζ expression despite comparable IL-34 expression to the WT mice. Compared to the WT mice, tubular injury and sirius red-stained fibrosis area were significantly attenuated in the KO mice kidney (9.0% ± 0.7 vs. 4.8% ± 0.7/HPF, p<0.001). The KO mice significantly suppressed the number of F4/80⁺ Mø, PDGF-β⁺ fibroblasts, and α-SMA⁺ myofibroblast in damaged kidneys of UUO by immunofluorescence (IF) analysis. Intrarenal mRNA levels for TGF-β, COL-1, fibronectin, Yim1/Chil3, and Timp-1 were lower in the KO mice. IF revealed significant suppression of intrarenal F4/80⁺CD206⁺ Mø infiltration in the KO mice. Flow cytometry analysis showed that the ratio of CD206/CD11c in the population of intrarenal CD11b⁺F4/80⁺ Mø was higher in the KO mice. In vitro, expressions of PTP-ζ were confirmed in TGF-β stimulated RAW264.7 cells and BMMs. Administration with TGF-β and rIL-34 significantly up-regulated the mRNA level for Timp-1 in RAW264.7 cells compared to TGF-β- and vehicle-treated group.

Conclusion

Up-regulation of PTP-ζ in the damaged kidneys is involved in the progression of renal fibrosis. IL-34/PTP-ζ pathway on Mø might skew Mø into M2-like Mø, contributing to renal fibrosis via enhancing profibrotic response.