Abstract: SA-PO0497
Obesity-Induced Metabolic Dysfunction Suppresses Intercalated Cell Innate Immunity
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Schwartz, Laura Link, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Salamon, Kristin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Wang, Xin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Simoni, Aaron A., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Vasquez Martinez, Gabriela, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Zepeda-Orozco, Diana, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Spencer, John David, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Obesity is a major risk factor for kidney disease and disrupts both systemic and renal metabolic homeostasis. In the context of infection, obesity is associated with increased incidence and severity of urinary tract infections (UTIs), including pyelonephritis. Intercalated cells (ICs) of the kidney collecting duct contribute to innate immune defense against uropathogens through urine acidification, antimicrobial peptide secretion, and phagocytosis. However, the metabolic pathways that support these immune functions remain incompletely defined. Moreover, the effects of obesity on IC metabolism and their consequences for antimicrobial defense in the kidney are not well understood.
Methods
Female C57Bl6/J mice were fed high-fat diet (HFD; 60% kcal from fat) or standard chow (10% kcal from fat) for 12 weeks. ICs were enriched from kidneys and analyzed by RNA sequencing. Seahorse assays measured IC glycolytic capacity and ATP production. Intracellular bacterial killing was quantified using a gentamicin protection assay. Acid handling was evaluated via acid loading with ammonium chloride and monitoring of urine and blood pH and electrolytes.
Results
Transcriptomic profiling revealed that ICs from HFD-fed mice expressed less vacuolar H+-ATPase, critical for urine and phagolysosome acidification. Genes involved in glycolysis, the Krebs cycle, and the electron transport chain were also suppressed. Seahorse assays confirmed reduced glycolytic capacity and oxygen consumption with HFD, though mitochondrial ATP production was increased, suggesting a compensatory metabolic shift. HFD ICs showed reduced expression of β-defensin and impaired bacterial killing in ex vivo assays. Acid-loaded HFD mice exhibited less effective urine acidification compared to SC-fed controls, consistent with impaired IC function.
Conclusion
These findings demonstrate that obesity reprograms the metabolic and immune landscape of kidney ICs, compromising their ability to acidify urine, clear pathogens, and mount an effective innate immune response. This work establishes a mechanistic link between IC metabolism and host defense and suggests that metabolic dysfunction in obesity contributes to increased susceptibility and severity of UTI. Targeting IC metabolism may represent a novel strategy to enhance renal immunity in obese individuals.
Funding
- NIDDK Support