|
| Status |
Public on Jun 10, 2020 |
| Title |
Rapamycin and dexamethasone during pregnancy prevents tuberous sclerosis complex associated cystic kidney disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex disease (TSC). The mechanisms underlying TSC cystic kidney disease remain unclear with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1 null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1 null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells, identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1 null kidneys. Dexamethasone administration during pregnancy decreased cyst formation not only by inhibiting the inflammatory response but also by interfering with the mTORC1 pathway. These results reveal novel mechanisms of cystogenesis in TSC disease and suggest new interventions prior to birth to ameliorate cystic disease in offspring.
|
| |
|
| Overall design |
RNA expression profile of proximal tubule cells extracted at E18.5 from WT, Six2 Cre Tsc1 Fl/Fl and Six2 Cre Tsc1 Fl/Fl mice subjected to Rapamycin treatment during embryogenesis. Each condition had three replicates.
|
| |
|
| Contributor(s) |
Volovelsky O, Nechama M |
| Citation(s) |
32484794 |
| |
| Submission date |
Jun 10, 2020 |
| Last update date |
Sep 09, 2020 |
| Contact name |
Morris Nechama |
| E-mail(s) |
Moris.Nehama@mail.huji.ac.il
|
| Phone |
+972586328141
|
| Organization name |
Hadassah Hebrew University Medical Center
|
| Department |
Pediatric
|
| Lab |
Pediatric Nephrology
|
| Street address |
Hadassah Medical Center, Ein Karem
|
| City |
Jerusalem |
| State/province |
Israel |
| ZIP/Postal code |
91120 |
| Country |
Israel |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (9)
|
| GSM4605289 |
Wild type proximal tubule cells repeat1 |
| GSM4605290 |
Wild type proximal tubule cells repeat2 |
| GSM4605291 |
Wild type proximal tubule cells repeat3 |
| GSM4605292 |
Six2 Cre Tsc1 fl/fl proximal tubule cells repeat 1 |
| GSM4605293 |
Six2 Cre Tsc1 fl/fl proximal tubule cells repeat 2 |
| GSM4605294 |
Six2 Cre Tsc1 fl/fl proximal tubule cells repeat 3 |
| GSM4605295 |
Six2 Cre Tsc1 fl/fl + Rapamycin treated proximal tubule cells repeat 1 |
| GSM4605296 |
Six2 Cre Tsc1 fl/fl + Rapamycin treated proximal tubule cells repeat 2 |
| GSM4605297 |
Six2 Cre Tsc1 fl/fl + Rapamycin treated proximal tubule cells repeat 3 |
|
| Relations |
| BioProject |
PRJNA638537 |
| SRA |
SRP266734 |
Less...
More...