Abstract

Abstract Background and Aims Recent studies demonstrate that klotho deficiency participate in various chronic kidney disease. However, it has not been fully assessed the influence of klotho in autoimmune kidney diseases. On the one hand, klotho is known to binds transforming growth factor β (TGFβ) receptor to antagonize its pathophysiological actions including renal fibrosis. On the other hand, TGFβ is required to generate and maintain regulatory T cells with inducing FOXP3, an important cell population for immunological tolerance. Method 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 was measured by tail-cuff method. Glomerular filtration rate was assessed using FITC-inulin. Four weeks later, the animals were killed to harvest the spleen and kidneys for analyses. Results Klotho supplementation suppressed blood pressure, 8-epi-prostaglandin F2a excretion and renal angiotensin II levels (p<0.05 for all) without changes in albuminuria and glomerular filtration rate 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 although klotho may not suite for the management of autoimmune kidney diseases, such as lupus and ANCA-related nephritis, klotho supplementation for dialysis patients could mitigate against the defect in cellular immunity and susceptibility to infections including tuberculosis and COVID-19.

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