Kidney Week

Abstract: FR-PO0159

Renoprotection by Semaglutide and Empagliflozin in ATTAC9-CKD, a Nondiabetic Low-Nephron Rat Model

Session Information

• Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Cardiovascular-Kidney-Metabolic Health

• 601 Cardiovascular-Kidney-Metabolic Health: Basic

Authors

• Ikeda, Takumi, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Takumi Ikeda

• Yamanaka, Shuichiro, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Shuichiro Yamanaka, MD, PhD

• Yamamoto, Shutaro, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Hinyokika, Minato, Tokyo, Japan

Shutaro Yamamoto, MD

• Matsui, Kenji, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Kenji Matsui, MD, PhD

• Yasui, Yukiko, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Yukiko Yasui, MD

• Shimada, Takahiro, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Takahiro Shimada, MD

• Matsumoto, Kei, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Kei Matsumoto, MD, PhD

• Yokoo, Takashi, Tokyo Jikeikai Ika Daigaku Igakubu Igakuka Jinzo Koketsuatsu Naikagaku, Minato, Tokyo, Japan

Takashi Yokoo, MD, PhD

Background

Per-nephron hyperfiltration after nephron loss drives CKD progression, but conventional models confound nephron overload with surgery, diabetes, or obesity. SGLT2 inhibitors slow non-diabetic CKD, but renal actions of GLP-1 receptor agonists in non-diabetic, non-obese nephron-overload CKD remain undefined.

Methods

We developed ATTAC9-CKD, a non-surgical, synchronized, severity-tunable Six2-iCaspase9 rat model of nephron-overload CKD. Nephron progenitor apoptosis was induced in utero by chemical inducer of dimerization at E17.5, a moderate phenotype selected after E15.5/E17.5 comparison. Of 43 enrolled rats, 41 completed 10-week follow-up after two non-renal procedure-related deaths. CKD rats received vehicle, empagliflozin, semaglutide, or combination (both empagliflozin and semaglutide) from 8 to 18 weeks; healthy controls received vehicle. Renal function, albuminuria, and glomerular morphology were assessed.

Results

At treatment initiation, CKD-vehicle rats showed moderate CKD versus healthy controls (serum creatinine 0.386 vs 0.290 mg/dL; BUN 52.8 vs 20.9 mg/dL; UACR 3.924 vs 0.104 g/gCr). Baselines were balanced among CKD arms. Treatments caused no major weight loss or hypotension. At treatment week 10, CKD-vehicle showed reduced Ccr/BW-eGFR versus healthy controls (0.36/0.36 vs 0.62/0.62 mL/min/100g; P=0.012/0.004). Empagliflozin alone showed intermediate filtration values. Semaglutide produced a clear structural renoprotective signal: the smallest glomerular diameter among CKD groups, the most favorable late-phase albuminuria trajectory, and numerically higher filtration than vehicle (Ccr 0.46; eGFR 0.42). Combination therapy showed the highest filtration among CKD groups (Ccr 0.57; eGFR 0.45), with Ccr approaching healthy-control levels, and most closely matched healthy controls across nonsclerotic tuft area and glomerular number index. Mixed-effects analysis revealed significant time-by-group interactions for Ccr and eGFR (P=0.002 and P=0.027).

Conclusion

By isolating nephron overload from metabolic and surgical confounders, ATTAC9-CKD revealed complementary renoprotection: semaglutide attenuated glomerular remodeling and albuminuria, while combination therapy produced the strongest filtration trajectory. ATTAC9-CKD establishes a preclinical platform for GLP-1RA and SGLT2i/GLP-1RA combination renoprotection beyond diabetic and obesity-associated CKD.