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| Status |
Public on Mar 21, 2020 |
| Title |
Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2∆podocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2∆podocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2∆podocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)—unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2∆podocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.
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| Overall design |
To explore the molecular mechanism of podocyte dysfunction in Tsc2∆podocyte mice, we conducted microarray analysis using the total RNA of primary podocytes isolated from Tsc2∆podocyte and control Tsc2flox/flox mice with or without rapamycin treatment (n = 4/each group).
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| Web link |
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229397
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| Contributor(s) |
Iwata W, Unoki-Kubota H, Kato H, Shimizu A, Matsumoto M, Imasawa T, Igarashi A, Matsumoto K, Noda T, Terauchi Y, Nangaku M, Kasuga M, Kaburagi Y |
| Citation(s) |
32191726 |
| Submission date |
Nov 13, 2017 |
| Last update date |
Mar 23, 2020 |
| Contact name |
Hiroyuki Unoki-Kubota |
| Organization name |
National Center for Global Health and Medicine
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| Department |
Department of Diabetic Complications, Diabetes Research Center, Research Institute
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| Street address |
1-21-1 Toyama
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| City |
Shinjuku-ku, Tokyo |
| ZIP/Postal code |
162-8655 |
| Country |
Japan |
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| Platforms (1) |
| GPL21163 |
Agilent-074809 SurePrint G3 Mouse GE v2 8x60K Microarray [Probe Name version] |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA418148 |
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