Kidney Week

Abstract: PO1521

Rapamycin and Dexamethasone in Pregnancy Prevents Tuberous Sclerosis Complex-Associated Cystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Mechanisms, Genetics, and Treatment
  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

• Nechama, Morris, Pediatric Nephrology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Morris Nechama,

• Makayes, Yaniv, Pediatric Nephrology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Yaniv Makayes,

• Resnick, Elad, Pediatric Nephrology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Elad Resnick,

• Meir, Karen, Division of Pathology, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Karen Meir,

• Volovelsky, Oded, Pediatric Nephrology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Oded Volovelsky,

Background

Renal cysts appear in the majority of tuberous sclerosis complex (TSC) patients and lead to a gradual loss of renal parenchyma. Chronic kidney disease is the leading cause of morbidity and mortality in adult TSC patients. The molecular pathways responsible for cyst formation and progression are not known and medical therapy is not available.

Methods

Homozygous deletion of TSC1 in Six2+ nephron progenitor cells was generated by mating TSC1^f/f females with Six2 Cre^tg/+ males. Kidneys were harvested at different embryonic ages for histopathology and western blotting for phosphorylated S6, F4/80, P65, c-Myc, and Ki-67. Proximal tubular cells were FACS-sorted using CD133 antibody for RNA sequencing and immunological phenotyping by F4/80. Rapamycin or dexamethasone was injected intraperitoneally during pregnancy.

Results

TSC1 deletion in nephron progenitor cells induced proximal tubule cell damage and cyst formation, starting as early as E15.5. mTORC1 hyperactivation, as well as macrophage infiltration in TSC null proximal tubules, led to tubular cell damage and cyst formation. Rapamycin prolonged survival by inhibiting mTORC1 and c-Myc activity in the embryonic kidneys and reducing the proliferation rate of PTCs. Administration of steroids during pregnancy prevented cyst formation in TSC offspring, not only by hindering the inflammatory process but also by downregulating mTORC1 activity.

Conclusion

TSC cystic kidney disease can be ameliorated during pregnancy by inhibiting mTOR activity and inflammation.