Abstract: TH-PO0115
Innovative Translational Models to Investigate AKI in the Context of Diabetes and Sepsis
Session Information
- AKI: Mechanisms - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Sanchez Navarro, Andrea, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Bolds, Ashley, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Rainford, Nicole Marie, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Hu, Xuzhen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Yuen, Peter S.T., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Star, Robert A., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
Acute kidney injury (AKI) in the setting of diabetes and sepsis remains a critical clinical issue, driven by the multifaceted interaction between metabolic and inflammatory stressors. To bridge the translational gap between bench and bedside, we established two complementary models designed to emulate key aspects of human disease: (1) an in vivo AKITA/CD-1 mouse model, incorporating non-immune β-cell dysfunction and genetic variability, and (2) an ex vivo platform using highly polarized proximal tubule cells to examine tubular injury in a physiologically relevant microenvironment.
Methods
In Aim 1, diabetic AKITA/CD-1 mice and wild-type CD-1 controls were subjected to cecal ligation and puncture (CLP) to induce sepsis. Renal function was evaluated using BUN levels, histopathology (PAS staining), and survival analysis. To study glomerular involvement, AKITA mice were crossbred with WT-1 hemizygous mice.
In Aim 2, primary proximal tubule cells from WT/CD-1 mice (mPPT) were cultured on decellularized kidney matrix within Transwell systems. TEER was used to assess barrier function, and polarization was verified via immunofluorescent staining for ZO-1 and Na/K ATPase. Cells were exposed to septic serum collected post-CLP from WT and AKITA mice, with TEER and LDH release analyzed to gauge injury and cell death.
Results
AKITA/CD-1 mice exhibited increased susceptibility to sepsis, with a mortality rate of 65% compared to 38% in controls, alongside hyperglycemia, elevated BUN, and glomerulosclerosis as compared to controls. Tubular damage was histologically evident early post-CLP and was higher in AKITA/CD-1 mice. In the ex vivo model, mPPT cells achieved functional polarization by day 7, confirmed through TEER demonstrated enhanced barrier integrity and immunofluorescence confirmed apical-basal polarity. Exposure to septic serum reduced TEER and elevated LDH levels, indicating compromised barrier integrity and cytotoxicity.
Conclusion
These novel in vivo and ex vivo platforms closely mirror the pathophysiological interplay between diabetes, sepsis, and AKI, underscoring the importance of incorporating co-morbidity models into renal research.
Ultimately, this research contributes to improving outcomes for kidney patients with complex comorbid conditions.
Funding
- NIDDK Support