Time restricted feeding improves mitochondrial function in proximal tubules and reduces progressive proteinuria in young non-diabetic obese Dahl salt-sensitive rats

Introduction: Prepubertal obesity (PPO) is a growing epidemic and major public health concern in the US. Obese children develop microalbuminuria and tubular injury. However, the role of obesity in the early progression of proteinuria during PPO remains poorly understood. Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats develop insulin resistance (IR) progressive proteinuria independent of diabetes before puberty. Renal proximal tubules (PTs) are the most energy-demanding segment of the kidney, responsible for reabsorbing the majority of filtered proteins and glucose. They primarily depend on fatty acid oxidation (FAO) as their main energy source. Recently, we observed impaired mitochondrial function and reduced FAO in the PTs of SS LepR mutant rats prior to puberty. Clinical studies suggest that time restricted feeding (TRF) improves insulin sensitivity and is considered beneficial in obese patients. However, the effects of TRF on PT energy metabolism and mitochondrial function during early development of obesity-induced renal injury have not been investigated. Hypothesis: Therefore, the current study examined whether TRF improves tubular mitochondrial function and energy metabolism and reduces renal injury in obese SS LepR mutant rats prior to puberty. METHOD: Four-week-old SS and SS LepR mutant rats were given either ad libitum access to food for 24 hours (control) or 8 hours during their active phase (TRF) for 4 weeks. Body weight, blood glucose and proteinuria were measured bi-weekly until rats reached 8 weeks of age. At the end of the study, a blood sample was collected to measure metabolic parameters. Kidneys were harvested to isolate proximal tubules for extracellular flux analysis via Seahorse to measure oxygen consumption rate (OCR; mitochondrial function) and extracellular acidification rate (ECAR; glycolysis). Sprague Dawley (SD) rats served as a control during the Seahorse analysis. Results: Body weight and food intake were significantly elevated in SS LepR mutant compared to SS rats, and TRF did not have an impact on both parameters. Fasting blood glucose were normal (≤120 mg/dL) in all of the groups. HOMA-IR (marker of IR) was significantly elevated in SS LepR mutant rats versus SS rats, and TRF only significantly reduced HOMA-IR in SS LepR mutant rats. Proteinuria was significantly higher in SS LepR mutant rats vs SS rats (401±51 vs. 27±4 mg/day, respectively; p<0.05 ), and TRF markedly reduced proteinuria in SS LepR mutant rats (144±19 mg/day; p<0.05 ). We observed a 2-fold increase in GFR in SS LepR mutant rats compared to SS rats indicating renal hyperfiltration. TRF prevented renal hyperfiltration in SS LepR mutant rats. Renal sodium glucose co-transporter 2 (SGLT2) expression were significantly elevated in SS LepR mutant rats compared to SS rats. In response to TRF, SGLT2 expression was only significantly reduced in SS LepR mutant rats. Moreover, KIM-1 excretion was increased in SS LepR mutant rats versus SS rats (151±48 vs. 38±4 ng/day, respectively; p<0.05 ), suggesting elevated tubular injury. TRF significantly reduced KIM-1 excretion in SS LepR mutant rats (56±19 ng/day; p<0.05 ). When measuring mitochondrial function, OCR was reduced in SS LepR mutant rats compared to SD rats, indicating impaired mitochondrial function, but TRF significantly increased OCR in SS LepR mutant rats. Additionally, ECAR was lower in both SS and SS LepR mutant rats compared to SD rats, with TRF having no effect on glycolysis in SS LepR mutant rats. Conclusion: Overall, these data suggest that TRF reduces proteinuria by potentially improving insulin sensitivity and PT mitochondrial function indicating TRF can be of great potential in obese children with early signs of renal injury. NIH/NIDDK – R01DK109133 NIH/NIA – R01AG057842 NIH/NIDDK – R56DK140968 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.