Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex–associated cystic kidney disease
Morris Nechama, … , Karen Meir, Oded Volovelsky
Morris Nechama, … , Karen Meir, Oded Volovelsky
Published June 2, 2020
Citation Information: JCI Insight. 2020;5(13):e136857. https://doi.org/10.1172/jci.insight.136857.
View: Text | PDF
Research Article Nephrology

Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex–associated cystic kidney disease

  • Text
  • PDF
Abstract

Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex (TSC) disease. 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 by not only inhibiting the inflammatory response, but also interfering with the mTORC1 pathway. These results reveal mechanisms of cystogenesis in TSC disease and suggest interventions before birth to ameliorate cystic disease in offspring.

Authors

Morris Nechama, Yaniv Makayes, Elad Resnick, Karen Meir, Oded Volovelsky

×

Figure 2

mTOR inhibition by rapamycin prevents proximal tubular damage and cyst formation and prolongs survival of Six2 Cretg/+ TSC1fl/fl mice.

Options: View larger image (or click on image) Download as PowerPoint
mTOR inhibition by rapamycin prevents proximal tubular damage and cyst f...
(A) Experimental time course. TSC1fl/fl females were mated with Six2 Cretg/+ TSC1fl/+ males. Rapamycin or vehicle (DMSO) was injected at the indicated gestational ages. Kidneys of Six2 Cretg/+ TSC1fl/fl P0 pups were removed. (B) Renal sections from Six2 Cretg/+ TSC1fl/fl mice were stained with H&E, IHC for LTL and Ki-67, and IF for phospho-S6 (pS6) and c-Myc. Scale bar: 50 μm. n = 3 in each group. (C) Quantitative analysis of cyst area and number of cyst per section as in B. *P < 0.05, compared with vehicle, DMSO (n = 5); rapamycin (n = 6). (D) Western blots of kidney extracts from control, Six2 Cre TSC1fl/+, Six2 Cretg/+ TSC1fl/fl mice treated with rapamycin or vehicle as in A, analyzed for pS6, GAPDH, and c-Myc, showing elevated pS6 and c-Myc expression in heterozygous and homozygous renal extracts compared with control and reduction in the expression of these proteins upon rapamycin treatment. (E) Quantification of the Western blot as in D. *P < 0.05, compared with control (WT). n = 3 in each group. (F) Kaplan-Meier curve showing improved survival rate of rapamycin-treated Six2 Cretg/+ TSC1fl/fl mice (n = 6), compared with DMSO (n = 6). (G) H&E staining of P14 offspring of rapamycin-treated Six2 Cretg/+ TSC1fl/fl mice as in A, demonstrating mononuclear infiltrate. The dashed circle indicates mononuclear inflammation site. Scale bar: 500 μm. n = 3. Unpaired t test was used for C and 1-way ANOVA statistical analysis was used followed by Duncan’s post hoc test for E. TSC, tuberous sclerosis complex; IF, immunofluorescent; LTL lotus tetragonolobus lectin.

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts