Kidney disease associated with pre-pubertal obesity initiates pathological alterations in the brain of Dahl salt-sensitive rats

Childhood/pre-pubertal obesity (PPO) is implicated in the development of chronic kidney disease (CKD), and there is evidence that PPO also increases the risk of developing Alzheimer disease (AD) later in life. In the current study, we aim to investigate the correlation between CKD and the development of AD-like pathology in a rat model of CKD associated with PPO. We hypothesize that systemic inflammation due to PPO exacerbates CKD and induces AD-like pathology in the brain at older age. In our preliminary studies, we utilized the Dahl salt sensitive leptin receptor mutant rat (SS LepR mutant), which is a novel model of PPO. 6-week-old Dahl salt-sensitive (SS) (control, n=3) and SS LepR mutant rats (n=5) were monitored for proteinuria every 3 weeks, for a 12-week period. Throughout the study, we observed significantly elevated proteinuria in SS LepR mutant rats (Week-6: 337±81 mg/day, Week-9: 371±147 mg/day, Week-18: 1920±318 mg/day) compared to SS rats (Week-6: 25±7 mg/day, Week-9: 35±39 mg/day, Week-18: 35±33 mg/day). At 18-week, creatinine levels were significantly higher in SS LepR mutant rats (1.5±0.5 mg/dL) versus SS rats (0.4±0.03 mg/dL) indicating CKD. Additionally, we found significant elevation of triglycerides in SS LepR mutant rats (5134±1211 mg/dL) compared to SS rats (79±21 mg/dL). To investigate the brain pathology, we performed immunochemical analysis (dot-blot assay) using A11 antibody to determine the levels of Amyloid-beta oligomers (Aβo). Our results show that there was tendency for Aβo levels to be increased in the brains from obese SS LepR mutant rats compared to SS. Finally, we tested the permeability of the blood-brain barrier to Evans blue dye and observed that the brain of SS LepR mutant rats was more permeable to the dye compared to SS rats as early as 8 weeks of age. Overall, these results indicate that PPO obesity not only increases the susceptibility to develop CKD but also causes Alzheimer-like pathology during the prepubescent stage. NIDDK (DK109133) and AG (AG057842) awarded to Jan M. Williams. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.