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Abstract: FR-PO595

Klotho Deficiency Induces Regulatory T Cells in Mice With Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Takenaka, Tsuneo, Kokusai Iryo Fukushi Daigaku Kohokai Group, Minato-ku, Tokyo, Japan
  • Inoue, Tsutomu, Saitama Ika Daigaku, Iruma-gun, Saitama, Japan
  • Miyazaki, Takashi, Saitama Ika Daigaku, Iruma-gun, Saitama, Japan
  • Miyazaki, Toshiaki, Saitama Ika Daigaku, Iruma-gun, Saitama, Japan
  • Hayashi, Matsuhiko, Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka, Shinjuku-ku, Tokyo, Japan
Background

Recent studies demonstrate that klotho deficiency participates in various chronic kidney disease. However, it has not been fully assessed the influence of klotho in autoimmune kidney diseases. Klotho is known to binds transforming growth factor β (TGFβ) receptor to antagonize its pathophysiological actions including renal fibrosis. Alternatively, TGFβ is required to generate and maintain regulatory T cells with inducing FOXP3, an important cell population for immunological tolerance.

Methods

NZBWF1 mice were used as a model of lupus nephritis. NZBWF1 mice were housed separately in metabolic cage, and divided into two groups (n=10 for each): one group was treated with daily subcutaneous injection of klotho protein (20 µg/kg/day), and the other received vehicle alone. Systolic blood pressure (SBP) was measured by tail-cuff method. Glomerular filtration rate (GFR) was assessed using FITC-inulin. Four weeks later, the animals were killed to harvest the spleen and kidneys for analyses.

Results

Klotho supplementation suppressed SBP, 8-epi-prostaglandin F2a excretion and renal angiotensin II levels (p<0.05 for all) without changes in albuminuria and GFR in NZBWF1 mice. Exogenous klotho protein supplementation increased serum klotho levels, urine klotho excretion, and endogenous renal expression of klotho in NZBWF1 mice (p<0.05 for all). Surprisingly, anti-double strand DNA antibody was slightly elevated in klotho-treated NZBWF1 mice (p<0.05). Glomerular pathology and interstitial cell infiltration were similar between 2 groups. The spleen tended to be greater in klotho-treated group, but statistical significance was not attained. In consistent, CD8+FOXP3+ T cells were unaltered between 2 groups. However, klotho supplementation reduced CD4+FOXP3+ T cells in spleen of NZBWF1 mice (p<0.05).

Conclusion

The present data indicated that klotho protein supplementation suppressed renal renin-angiotensin system, ameliorating blood pressure and oxidative stress. Our results suggest that klotho supplementation worsened auto-antibody, possibly by inhibiting TGFβ with resultant deterioration in regulatory T cells. The present findings implicate that while klotho may not suite for the management of autoimmune kidney diseases, klotho supplementation for dialysis patients could partly reverse the defect in cellular immunity and susceptibility to infections.

Funding

  • Government Support – Non-U.S.