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Abstract: FR-PO923

Angiotensin II Receptor Blocker Blocks Spreading Podocyte Damage in a Partial Podocytectomy Model

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Okabe, Masahiro, Tokai University School of Medicine, Isehara, Japan
  • Yamamoto, Kazuyoshi, Tokai University School of Medicine, Isehara, Japan
  • Miyazaki, Yoichi, The Jikei University School of Medicine, Tokyo, TOKYO, Japan
  • Yokoo, Takashi, The Jikei University School of Medicine, Tokyo, TOKYO, Japan
  • Matsusaka, Taiji, Tokai University School of Medicine, Isehara, Japan
Background

We established a new mosaic mouse model in which approximately 50% of podocytes express hCD25 and tdTomato whereas the other podocytes express EGFP but not hCD25. After the injection with hCD25-targeting immunotoxin, LMB2, not only hCD25-positive but also hCD25-negative podocytes were injured, and the mice developed global sclerosis. These indicated that injury incurred in a fraction of podocyte population causes secondary damage in other initially intact podocytes. This phenomenon may underlie progressive deterioration of chronic kidney diseases. In the present study, we tested whether this new mosaic ‘partial podocytectomy’ model can be used to evaluate renal protective effects of candidate drugs. As a proof of concept, we investigated the effect of angiotensin II receptor blocker (ARB), a well-established reno-protector, in this model.

Methods

Twelve female mosaic mice from 28 to 35 weeks of age were injected with LMB2. One day later, they were treated with losartan (0.5g/L in drinking water) (ARB group, n=6) or with 5% sucrose (Control, n=6). Fourteen days after LMB2 injection, kidneys were harvested and analyzed.

Results

Control mosaic mice developed severe glomerular damage with early sclerosis, adhesion, and hyalinosis, and dilated tubules with protein casts. These were markedly ameliorated in the ARB group. Glomerular injury index (in 0 (normal)-4 scales) was 3.3±0.30 (SE) in the Control group, which was improved to 0.13±0.083 in the ARB group (p<0.01). In addition, nephrin staining was more preserved (7.7±0.2 vs 3.0±1.0 in 0-8 (normal) scales, p<0.01) and desmin-positive podocytes were less observed (29±7% vs 74±11%, p=0.026) in the ARB group than the Control group. Importantly, EGFP-labeled podocytes, which do not carry hCD25 gene therefore are not directly injured by LMB2, were also secondarily injured, and the number decreased from 3.8±0.14 to 1.4±0.23 per a glomerulus after LMB2 injection in the Control group. The EGFP-positive podocytes were significantly more preserved in the ARB group (from 3.9±0.3 to 2.9±0.2, p<0.01).

Conclusion

Thus, our mosaic mouse model can visualize and evaluate secondary podocyte injury, and we have herein demonstrated that ARB attenuates the secondary podocyte injury.

Funding

  • Government Support - Non-U.S.