Kidney Week

Abstract: SA-PO0940

Acute and Chronic Renal Injuries Based on the Renal Pelvis-Kidney Pathological Axis Observed in C57BL6/N-Upk2em1(DTR) Mice

Session Information

• Pathology: Updates and Insights
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1800 Pathology and Lab Medicine

Authors

• Namba, Takashi, Hokkaido University, Faculty of Veterinary Medicine, Sapporo, Hokkaido, Japan

Takashi Namba, PhD, DVM

• Oe, Sao, Hokkaido University, Faculty of Veterinary Medicine, Sapporo, Hokkaido, Japan

Sao Oe

• Otani, Yuki, Hokkaido University, Faculty of Veterinary Medicine, Sapporo, Hokkaido, Japan

Yuki Otani, PhD, DVM

• Ichii, Osamu, Hokkaido University, Faculty of Veterinary Medicine, Sapporo, Hokkaido, Japan

Osamu Ichii, DVM, PhD

Background

The urothelium of urinary tract protects its underlying tissues from urine. However, this urine-urothelium barrier (UUB) can be disrupted. For instance, obstructive uropathy increases intra-luminal pressure within the urinary tract, leading to renal fornix rupture, subsequently causing inflammation of the renal pelvis (RP). The mechanisms how extravasated urine causes kidney damage remain unclear. Here, we report the establishment of a novel murine model to investigate renal injury induced by UUB dysfunction.

Methods

We generated a novel knock-in mouse model, C57BL6/N-Upk2^em1(DTR)(Upk2-DTR), expressing the human diphtheria toxin receptor (hDTR) under the control of the uroplakin 2 (Upk2) promoter, to enable urothelium-specific expression. For short-term injection (SI) models, heterozygous Upk2-DTR mice and their wild-type (WT) were intraperitoneally injected with a single dose of diphtheria toxin (25 ng/g) and sacrificed 3 days post-injection. For long-term injection (LI) models, the mice received repeated injections (16.7 ng/g) on days 0, 3, 10, 17, and 24, and were sacrificed on day 28. Renal functions, renal histopathology, and mRNA levels of molecules related to inflammation and renal injury were evaluated.

Results

The RP urothelium in Upk2-DTR mice with SI was damaged with cellular proliferation and collagen 17A1 induction (an urothelial injury marker). These Upk2-DTR mice exhibited significantly lower body weight, higher blood urea nitrogen (BUN) and serum creatinine levels, as well as elevated renal mRNA levels of Havcr1, Il1f6, Il6, and Cxcl2 compared to WT mice. Importantly, KIM1⁺ injured proximal tubules and IBA1⁺ macrophages were predominantly observed in the renal parenchyma adjacent to the RP. Upk2-DTR mice with LI also exhibited significantly lower body weight, elevated BUN levels, collagen 17A1 expression in the RP urothelium and renal mRNA levels of Havcr1, Il1f6, and Il1b compared to WT mice.

Conclusion

Upk2-DTR mice with SI and LI developed acute and chronic tubulointerstitial injuries, respectively, following UUB disruption. We have previously found urine leakage, leading to CXCL2⁺ macrophage induction and urinary tract-associated lymphoid structure development. This Upk2-DTR mice can be a novel model for further elucidating the pathological roles of extravasated urine in the RP-kidney pathological axis.

Funding

• Private Foundation Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025k27kqa8q