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 revealed 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 to anti-IgG treated DIO mice. Single cell RNA sequencing data revealed 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 discovered that TRF reverses 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
