Kidney Week

Abstract: SA-PO856

CD11c-Specific Ablation of SHP-1 Results in Renal Fibrosis with Age

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Watanabe, Mitsuharu, Gunma University Graduate School of Medicine, Maebashi, Japan

Mitsuharu Watanabe,

• Kaneko, Yoriaki, Gunma University Graduate School of Medicine, Maebashi, Japan

Yoriaki Kaneko,

• Kinoshita, Masato, Gunma University Graduate School of Medicine, Maebashi, Japan

Masato Kinoshita,

• Ohishi, Yuko, Gunma University Graduate School of Medicine, Maebashi, Japan

Yuko Ohishi,

• Sakairi, Toru, Gunma University Graduate School of Medicine, Maebashi, Japan

Toru Sakairi,

• Ikeuchi, Hidekazu, Gunma University Graduate School of Medicine, Maebashi, Japan

Hidekazu Ikeuchi,

• Nojima, Yoshihisa, Japan Red Cross Maebashi Hospital, Maebashi, Japan

Yoshihisa Nojima,

• Hiromura, Keiju, Gunma University Graduate School of Medicine, Maebashi, Japan

Keiju Hiromura,

Background

Renal mononuclear phagocytes (rMoPh) which express traditional macrophage and dendritic cell marker, F4/80 and CD11c respectively, have attracted attention because of their immunoregulatory roles in healthy and diseased kidneys (JASN 23:194, 2012). We have previously generated CD11c-specific SHP-1 conditional knockout mice (SHP-1 CKO) which lack a protein tyrosine phosphatase, SHP-1, and reported that they spontaneously develop tubulointerstitial nephritis characterized by the marked accumulation of CD11c⁺F4/80⁺ double-positive rMoPh, (J Immunol 2012, ASN 2016). In the present study, we further analyzed the kidney of SHP-1 CKO to clarify the precise contribution of rMoPh to the development of the nephritis.

Methods

The kidneys obtained from SHP-1 CKO and its control mice (Ctrl) at the age of 40 weeks and were analyzed; in particular, the expressions of vimentin, a marker of mesenchymal cells, and α-smooth muscle actin (α-SMA), a marker of myofibroblasts, were evaluated by immunohistochemistry. Collagen-digested renal mononuclear cells from SHP-1 CKO and Ctrl were analyzed by flow cytometry (FCM).

Results

Masson’s trichrome and Sirius Red staining showed that the area of renal fibrosis was significantly increased in SHP-1 CKO compared to Ctrl. The immunohistochemical analysis revealed marked expression of vimentin and moderate expression of α-SMA in tubulointerstitial area of SHP-1 CKO. Intracellular FCM staining revealed majority of vimentin as well as α-SMA positive-cells were CD11c⁺F4/80⁺ double-positive rMoPh in SHP-1 CKO. A small number of CD45^-, non-hematopoietic cells, were positive for vimentin or α-SMA, but not significantly different compared to Ctrl. To confirm the efficacy of depletion of SHP-1, we examined the SHP-1 expression in rMoPh by intracellular FCM staining. About 70% of CD11c⁺F4/80⁺ rMoPh did not express SHP-1. These results suggested that SHP-1 depletion in CD11c⁺F4/80⁺ rMoPh led to the upregulation of vimentin and α-SMA, and directly caused renal fibrosis.

Conclusion

Depletion of SHP-1 in CD11c⁺F4/80⁺ rMoPh induces renal tubulointerstitial nephritis and fibrosis with age. In addition, transformation of CD11c⁺F4/80⁺ rMoPh into myofibroblasts could be involved in underlying mechanisms of renal fibrosis.