Abstract: PO1548
The Effect of Trehalose on Autophagy-Related Proteins and Cyst Growth in a Hypomorphic Pkd1 Mouse Model of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Session Information
- Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Atwood, Daniel, Univ Colorado, Aurora, Colorado, United States
- Pokhrel, Deepak, Univ Colorado, Aurora, Colorado, United States
- Brown, Carolyn Nicole, Univ Colorado, Aurora, Colorado, United States
- Hopp, Katharina, Univ Colorado, Aurora, Colorado, United States
- Edelstein, Charles L., Univ Colorado, Aurora, Colorado, United States
Background
There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) is a natural sugar that is used as a food additive. TRE increases protein stability, aggregate clearance and autophagy in neurodegenerative diseases.TRE treatment in wild type (WT) mice resulted in increased expression in the kidney of Atg12-5 complex and Rab9a (Table), autophagy-related proteins that play a role in the formation of autophagosomes. Thus, the aim of the study was to determine the effect of TRE on cyst growth and autophagy-related proteins, in the Pkd1RC/RC (RC) mouse model.
Methods
Autophagy proteins determined by immunoblot analysis. Male RC mice were treated with TRE from 50-120 days of age.
Results
In RC kidneys, expression of the Atg12-5 complex was inhibited by TRE resulting in increased free Atg12. TRE was unable to rescue the deficiency of the Atg12-5 complex. Rab9a was decreased in RC and unaffected by TRE. The TRE-induced increase in p62, a marker of autophagic cargo, that was seen in WT was blocked in RC kidneys. In RC kidneys, there were decreases in autophagy-related proteins (Atg12-5 complex, Atg5, Atg16L1), decreased Rab9a and increased mTORC1 (pS6, p-mTOR) proteins. 2 kidney/body weight ratio (2K/BW), cyst index/count, BUN were not different in TRE vs. Veh treated RC kidneys.
Conclusion
The autophagy phenotype in RC kidneys was characterized by decreases in essential autophagy related proteins. TRE increased Atg12-5 complex, Rab9a and p62 in WT kidneys, but was unable to rescue the deficiency in autophagy proteins or suppress mTORC1 in RC kidneys and did not protect against cyst growth.
Densitometry units/GAPDH *P<0.05, **P<0.01. ***P<0.001
| WT | WT+TRE | RC | RC+TRE | |
| ATG12-5 | 0.4 | 0.9 | 0.05** | 0.05** |
| Free ATG12 | 0.1 | 0.1 | 0.8*** | 0.9*** |
| Rab9a | 0.7 | 1.0 | 0.3* | 0.3* |
| p62 | 0.4 | 1.0** | 0.1 | 0.1 |
| ATG16L | 1.5 | 1.5 | 0.8* | 0.5* |
| ATG5 | 1.4** | 1.4** | 0.8 | 1.0 |
| pS6 | 0.6 | 0.7 | 2.1** | 2.4** |
| p-mTOR | 1.1 | 1.1 | 1.9** | 2.3** |
| 2K/BW (%) | 2.7 | 3.0 | ||
| Cyst index/number | 14/330 | 16/300 | ||
| BUN (mg/dL) | 23 | 24 |
Funding
- Veterans Affairs Support