NLRP3 INFLAMMASOME IS INVOLVED IN SEX DIFFERENCES IN RENAL TUBLOINTERSTITIAL FIBROSIS.

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NLRP3 INFLAMMASOME IS INVOLVED IN SEX DIFFERENCES IN RENAL TUBLOINTERSTITIAL FIBROSIS.

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Co-author 1

Mariko Kamata m.kamata@med.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan *

Co-author 2

Yoshiya Ito yito@kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 3

Sakura Motohashi motohashi.sakura@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 4

Aran Nagasawa nagasawa.aran@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 5

Momona Sunahara sunahara.momona@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 6

Hikaru Takada takada.hikaru@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 7

Saori Hokama hokama.saori@kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 8

Takahiro Honda honda.takahiro@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 9

Seishiro Akinaga akinaga2@kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 10

Takuya Yamazaki yamazaki.takuya@st.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 11

Kanako Hosono hosono@med.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 12

Hideki Amano hideki@med.kitasato-u.ac.jp Kitasato University School of Medicine Department of Pharmacology Sagamihara Japan -

Co-author 13

Co-author 14

Co-author 15

Introduction

Compared to men, women progress more slowly to end-stage renal failure in kidney disease, suggesting that estrogen may inhibit renal fibrosis. However, the underlying mechanism remains unclear. Chronic kidney disease (CKD) progresses to end-stage renal failure through worsening tubulointerstitial fibrosis, exacerbated by macrophage-inflammasome activation, which induces the secretion of inflammatory cytokines. Therefore, we examined sex differences in tubulointerstitial fibrosis and macrophages in mice using the unilateral ureteral obstruction (UUO) model, a model of renal fibrosis.

Methods

A UUO model was created in male and female mice. Kidneys were harvested on day 7 and evaluated for fibrosis and macrophages using Sirius Red staining, immunohistochemistry, and real-time PCR.

Results

The gene expression of fibrosis-related factors Col1a1 and Acta2, the fibrosis-promoting factor Fgf2, and the Sirius Red-positive area were significantly suppressed in females compared to males. Gene expression of the macrophage marker F4/80 and the inflammatory macrophage-related genes Il-1β and II-6 was significantly lower in females; however, there was no difference in the expression of anti-inflammatory macrophage-related genes.To investigate the inhibitory effect of estrogen on renal fibrosis, the ovaries were removed from mice and compared with those of the control group. In the fibrosis assessment, the gene expression of Col1a1, Acta2, and Fgf2 was significantly higher in the ovariectomized group, while the expression of inflammatory macrophage-related genes Il-1β and Nos2 was significantly higher in the ovariectomized group. Since NLRP3 inflammasome has been reported to exacerbate renal fibrosis in UUO kidneys via IL-1β production, we administered the NLRP3 inflammasome inhibitor MCC950 to male and female mice in a UUO model and evaluated fibrosis. The gene expression of Col1a1, Acta2, and Fgf2 was significantly suppressed in the MCC950-treated group compared to the control group in males, but no significant difference was observed in females. Furthermore, the gene expression of F4/80 and Il-1β was significantly suppressed in the MCC950-treated group in males, but no significant difference was observed in females.

Conclusion

Fibrosis was significantly suppressed in female UUO kidneys compared to male UUO kidneys, suggesting that the inhibitory effect of estrogen on the NLRP3 inflammasome is involved.

Kewords