Timing of Diet and Kidney Pathophysiology in Diet-Induced Obesity

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SUMMARY Obesity is particularly severe in terms of escalating kidney dysfunction, disrupted body fluid homeostasis, kidney injury. Our diet-induced obesity (DIO) mouse model (20-wk, ad lib 45% high fat diet, HFD) dampened feeding cycles, impaired kidney mitochondrial metabolism, amplified kidney medullary oxidative stress and excretion of reactive oxygen species (ROS), as well as increased medullary interstitial fibrosis compared to mice on a normal diet. Remarkably, restoring feeding-fasting cycles through time-restricted food intake (TRF), without altering total caloric intake during the final 2 weeks of DIO, re-established whole body diurnal energy metabolism, normalized excretion of oxidants and renal injury markers, as well as abolished renal interstitial fibrosis and T cell infiltration. These remarkable findings clearly indicate that feeding-fasting cycles are critical for kidney health in obesity. The goal of the proposed studies is to determine specifically how timing of feeding-fasting cycles impacts kidney mitochondrial respiration, inflammation and fibrosis in obesity. Our central hypothesis states that timed feeding- fasting ameliorates DIO-driven kidney fibrosis by reinstating kidney mitochondrial function and reducing T cell activation and migration to the kidney. Prior studies suggest that the clock gene, Bmal1, regulates mitochondrial function, but whether this is critical for DIO-induced metabolic dysfunction in the kidney is unknown. Our new data reveal significant, time-of-day differences in mitochondrial respiration in renal medulla of Bmal1 knockouts compared to wildtype littermates. In our model of DIO, we observed that circadian rhythms in whole body energy metabolism are lost but restored by TRF. We also observed that DIO causes a phase shift in the circadian molecular clock in the kidney. We posit that the mechanisms responsible for the TRF effects in obesity to restore kidney mitochondrial metabolism is via re-establishing clock activity and suppressing ROS production. Furthermore, TRF abolishes kidney interstitial fibrosis and kidney vasa recta-associated T cell infiltration in obese mice suggesting that timed feeding-fasting promotes kidney health by reducing kidney T cell inflammation. Our new data found that endothelium-derived ET-1 specifically mediates kidney pro-inflammatory CD4+T cell activation. We show that gut pro-inflammatory T cell activation and cytokine production is ETA dependent and that CD4+T cells in the gut migrate to peripheral tissues. Thus, we further propose that TRF mitigates DIO-driven kidney medullary fibrosis by reinstating diurnal rhythms of kidney endothelium-derived ET-1 with T cell clock activity and ETA dependent T cell activation and migration from the gut to the kidney. Studies will address two specific aims: First, to test the hypothesis that TRF reduces kidney fibrosis in DIO through Bmal1 mediated restoration of mitochondrial function and reduced mitochondrial-derived ROS. Second, to test the hypothesis that TRF mitigates DIO-driven kidney fibrosis by reinstating physiological endothelium-derived ET-1 in the kidney with T cell activation.