Abstract: TH-PO1166
A Novel, Scalable Rat Model of Glomerular Hyperfiltration CKD via Inducible Nephron Progenitor Cell Ablation
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Yamamoto, Shutaro, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Yamanaka, Shuichiro, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Ikeda, Takumi, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Morimoto, Keita, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Matsumoto, Kei, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Kimura, Takahiro, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
- Yokoo, Takashi, Tokyo Jikeikai Ika Daigaku, Tokyo, Japan
Background
Nephron overload is the final common pathway in chronic kidney disease (CKD) progression. Efficient, uniform models of glomerular hyperfiltration are scarce, impeding drug discovery. Conventional 5/6 nephrectomy models suffer from invasiveness, variability, and poor scalability. We developed a novel, non-invasive, scalable rat model of hyperfiltration CKD.
Methods
We generated a novel CKD model using Six2-iCaspase9 transgenic rats expressing inducible Caspase9 via the nephron progenitor cell (NPC)-specific Six2 promoter. A single IP injection of a chemical inducer of dimerization (CID) was administered to pregnant dams at E13.5-E19.5 to induce targeted NPC apoptosis for graded nephron reduction. CID-treated rats (Tg+; CKD model) were compared with vehicle/non-transgenic controls (Tg-). Optimized in vitro fertilization (IVF) ensured scalable embryo production. CKD was assessed by serum creatinine (sCr), blood urea nitrogen (BUN), urine albumin-to-creatinine ratio (UACR), glomerular diameter, glomerulosclerosis, and interstitial fibrosis. eGFR was calculated (sCr, BUN, body weight).
Results
Rats subjected to CID treatment at E17.5 developed characteristic features of CKD by 8 weeks of age. Tg+ had significantly higher BUN (p<0.01) and sCr (p<0.05) than Tg-. eGFR in Tg+ (1830±149μL/min, n=29) was 40% lower than Tg- (3062±190μL/min, n=8; p<0.0001). Tg+ also showed marked albuminuria, indicating glomerular damage. Glomerular diameter in Tg+ (163±7μm, n=16) was 1.9-fold greater than Tg- (84±3μm, n=25; p<0.0001), consistent with hypertrophy. Histology confirmed glomerulosclerosis and interstitial fibrosis. Furthermore, CID timing (E13.5-E19.5) allowed for graded control of CKD severity, ranging from neonatal lethality to milder phenotypes. IVF enabled reproducible, large-scale, uniform CKD model rat generation.
Conclusion
The inducible NPC ablation model utilizing Six2-iCaspase9 transgenic rats provides a non-invasive, scalable, and severity-controllable platform that effectively recapitulates key aspects of glomerular hyperfiltration-associated CKD. This novel model, with its unprecedented control and scalability, promises to accelerate CKD research and drug discovery. Efficacy studies of SGLT2 inhibitors and GLP-1 receptor agonists in this model are underway.
Funding
- Government Support – Non-U.S.