Kidney Week

Abstract: FR-OR113

Dysfunction of Proteasome in Podocytes Results in CKD

Session Information

• Stress Signaling and Fibrosis
  November 03, 2017 | Location: Room 277, Morial Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: Cell Biology

• 201 Cell Signaling, Oxidative Stress

Authors

• Makino, Shinichi, Kyoto University Graduate School, Kyoto, kyoto, Japan

Shinichi Makino, MD

http://www.tmk.med.kyoto-u.ac.jp/index_English.html

• Shirata, Naritoshi, Mitsubishi Tanabe Pharma Corporation, Toda, Japan

Naritoshi Shirata,

• Nonaka, Kanae, Kyoto University Graduate School of Medicine, Kyoto, Japan

Kanae Nonaka,

• Yanagita, Motoko, Kyoto University Graduate School of Medicine, Kyoto, Japan

Motoko Yanagita,

• Asanuma, Katsuhiko, Chiba University Graduate School of Medicine, Chiba, Japan

Katsuhiko Asanuma,

Background

Ubiquitin-proteasome(UP) and autophagy had been known as major intracellular degradation systems. The importance of autophagy in podocyte has already been reported, however, the role of UP has not well been understood.

Methods

To investigate the role of UP in podocyte, we generated podocyte-specific proteasome knockout mice (Rpt3^pdKO) by deletion of Rpt3, which is essential for construction of 26S proteasome, using Cre-loxP system under the regulation of the podocyte specific podocin promoter. To evaluate autophagy activity, LC3 was visualized by crossing with GFP-LC3 transgenic mice.

Results

Rpt3^pdKO mice developed albuminuria starting at 4 weeks of age and increased significantly higher levels compared with their Rpt3^Ctrl littermates on 8weeks of age. The ratio of sclerotic glomeruli and serum creatinine levels were significantly increased. The KO mice exhibited a significantly lower survival ratio than the littermates due to severe renal failure.
Ubiquitinated proteins were accumulated and the oxidative stress marker 8OHdG intensity was increased in podocytes of Rpt3^pdKO mice. Expressions of p53 and cleaved caspase3 to regulate apoptosis were increased in podocytes of the KO mice. On the other hand, LC3 positive dots in the KO podocytes were not increased, and accumulation of p62 which is detected in autophagy failure, was seen in the KO podocytes.

Conclusion

Ubiquitin-proteasome plays an important role in podocytes, resulting in severe renal failure.

Funding

• NIDDK Support –