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Time-restricted feeding reverses kidney fibrosis through reducing CD8+ T cell infiltration in obese mice
Claudia J. Edell, John D. Erickson, Xiaofen Liu, Savannah C. Walker, Jackson Colson, Michael Heim, Pranav Nagila, Kyle H. Moore, Keri M. Kemp, Kelly Hyndman, Selene Meza-Perez, Troy D. Randall, Annye P. Bennett, Anna G. Sorace, Yu-Hua Dean Fang, David M. Pollock, Carmen De Miguel, Julienne L. Carstens, Jennifer S. Pollock
Claudia J. Edell, John D. Erickson, Xiaofen Liu, Savannah C. Walker, Jackson Colson, Michael Heim, Pranav Nagila, Kyle H. Moore, Keri M. Kemp, Kelly Hyndman, Selene Meza-Perez, Troy D. Randall, Annye P. Bennett, Anna G. Sorace, Yu-Hua Dean Fang, David M. Pollock, Carmen De Miguel, Julienne L. Carstens, Jennifer S. Pollock
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Research Article Inflammation Nephrology

Time-restricted feeding reverses kidney fibrosis through reducing CD8+ T cell infiltration in obese mice

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Abstract

Obesity is a major risk factor for chronic kidney disease. Time-restricted feeding (TRF) shows promise to reduce kidney inflammation in chronic kidney disease. We hypothesized that TRF blunts kidney fibrosis in obese mice by mitigating T cell inflammation. We used a diet-induced obese mouse model fed a high-fat diet (DIO; 45% fat) ad libitum for 18 weeks followed by 2 weeks of TRF or ad libitum high-fat feeding. We found that TRF reversed kidney fibrosis as well as reduced kidney CD8+ T cells in DIO mice. Our study also reveals that DIO mice had increased kidney CD8+ T cell infiltration from the small intestine that was blunted with TRF. Furthermore, anti-CD8 intervention in DIO showed reduced kidney fibrosis and damage compared with anti-IgG–treated DIO mice. Single-cell RNA-seq data reveal that DIO increased, while TRF reduced, the frequency of a specific cluster of CD8+ T cells that featured high expression of exhaustion/activation genes. Spatial analyses showed DIO mice had significant infiltration of PD-1+CD8+ T cells near CD31+ endothelial cells that was diminished by TRF. In conclusion, this study shows that TRF reversed kidney fibrosis through reducing CD8+ T cell infiltration in obese mice.

Authors

Claudia J. Edell, John D. Erickson, Xiaofen Liu, Savannah C. Walker, Jackson Colson, Michael Heim, Pranav Nagila, Kyle H. Moore, Keri M. Kemp, Kelly Hyndman, Selene Meza-Perez, Troy D. Randall, Annye P. Bennett, Anna G. Sorace, Yu-Hua Dean Fang, David M. Pollock, Carmen De Miguel, Julienne L. Carstens, Jennifer S. Pollock

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Figure 1

TRF reverses renal fibrosis and tubular damage in DIO mice.

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TRF reverses renal fibrosis and tubular damage in DIO mice.
(A) Experime...
(A) Experimental design of dietary protocol with 18 weeks of ad libitum feeding before 2 weeks of ad libitum feeding or TRF. (B) Longitudinal weight gain, measured weekly, from start of normal or high-fat diet until end of dietary protocol. (C) Twenty-four–hour kilocalorie (kcal) intake for ND, DIO, and DIO+TRF groups during 2-week intervention period. (D) Kidney weight from all 3 experimental groups at the end of the 20-week protocol. (E) ADC shown for ND, DIO, and DIO+TRF at 18 weeks and 20 weeks of diet and change in ADC from 18 weeks to 20 weeks for ND, DIO, and DIO+TRF. (F) Representative 40× images of the kidney outer medulla (black arrow pointing to vasa recta bed). (G) Histological fibrosis scores for vasa recta fibrosis. (H) Representative 40× images of the kidney outer medulla (black arrows pointing to vasa recta bed) stained with Masson’s blue trichrome. (I) Histological fibrosis scores for vasa recta associated interstitial fibrosis. (J) Representative 40× images of the kidney cortex stained at 18 weeks (black arrows pointing to tubulointerstitial fibrosis). (K and L) Quantification of cortical tubulointerstitial fibrosis (K) and glomerulosclerosis (L) at week 18. (M) Representative 40× images of the kidney cortex stained at 20 weeks (black arrows pointing to tubulointerstitial fibrosis). (N and O) Quantification of cortical tubulointerstital fibrosis (N) and glomerulosclerosis (O) at week 20. Two-way ANOVA was used to compare time of day and dietary groups with Tukey’s post hoc test (E, I, N, and O); 1-way ANOVA in C–E; and 2-tailed t test in G, K, and L. Gray background is used for ZT13–15 (dark phase); white background is used for ZT1–3 (light phase). Scale bars are 20 µm.

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