Abstract: FR-PO985
A Novel Mouse Model: Authentic Reproduction of Human CKD
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Deng, Qiwen, Stanford University School of Medicine, Stanford, California, United States
- Wernig, Gerlinde, Stanford University School of Medicine, Stanford, California, United States
Background
Animal models are vital for understanding chronic kidney disease (CKD) pathogenesis and developing effective treatments. However, existing models fail to accurately replicate typical changes in human CKD. We present a novel mouse model faithfully recapitulating key aspects of human chronic kidney diseases.
Methods
We employed the Pax8-rtTA transgenic mouse model with high expression of the reverse tetracycline-dependent transactivator (rtTA) in kidney tubules under the control of the Pax8 promoter. Through crossing Pax8-rtTA mice with tetracycline-responsive Jun mice, an inducible CKD-JUN model was established, resulting in Jun overexpression specifically in kidney tubules upon doxycycline administration. Control mice were generated without doxycycline or Jun expression. Ten-week-old mice received continuous doxycycline (0.5 mg/ml) in their drinking water for 2 or 12 weeks. Body weight and kidney size were measured. Blood urea nitrogen (BUN) and serum creatinine were determined. Kidney tissue was subjected to H&E, PAS, and Trichrome staining to evaluate histological changes. Renal inflammation was evaluated through Luminex analysis of cytokine secretion in serum and kidney tissue supernatants, along with assessment of immune cell infiltration.
Results
Following a 2-week induction, histological analysis confirmed acute tubular necrosis in CKD-JUN mice, validating early tubular injury due to Jun induction. After a 12-week induction, both male and female CKD-JUN mice exhibited stable kidney impairment, with males showing a higher propensity for chronic kidney injury and faster CKD progression. CKD-JUN mice displayed decreased body weight, reduced kidney size, elevated BUN and creatinine levels indicative of renal function failure, increased pro-fibrotic inflammatory cytokines in serum and kidney tissue supernatants, and histological signs of glomerular hypertrophy, tubular dilation, interstitial fibrosis, and inflammatory cell infiltration. Other organs in CKD-JUN and Control mice showed no significant differences, confirming the kidney-specific nature of this model. These findings closely resemble characteristic renal abnormalities observed in human CKD.
Conclusion
Our CKD-JUN mouse model faithfully recapitulates essential clinical and histological characteristics of human CKD, making it a reliable and invaluable tool for studying CKD mechanisms and evaluating therapeutic interventions.