ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: FR-PO974

Extracellular Vesicle Induction of Cortical Collecting Duct Cell Growth

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Bissler, John J., Le Bonheur Children's Hospital and St. Jude Children's Research Hospital, Memphis, Tennessee, United States
  • Barone, Sharon L., University of Cincinnati, Cincinnati, Ohio, United States
  • Zahedi, Kamyar A., University of Cincinnati, Cincinnati, Ohio, United States
  • Soleimani, Manoocher, University of Cincinnati, Cincinnati, Ohio, United States

Tuberous sclerosis complex (TSC), a genetic tumor suppressor syndrome, is caused by inactivation of either TSC1 or TSC2 genes. Renal manifestations include early onset chronic kidney disease, angiomyolipomata and multiple patterns of renal cystic disease. The mechanism of cystogenesis has been assumed to be somehow linked to the PKD1 gene that is adjacent to the TSC2 gene, though the precise mechanism remains unclear.


We used transgenic animals with aquaporin-2 promoter driven Cre recombinase and renin-1c promoter regulated Cre recombinase to specifically inactivate the Tsc2 and Tsc1 genes in principal cells (Aqp2CreTsc2) and renal pericytes (Ren1cCreTsc1), respectively. We also used CRISPR/CAS9 technology to disrupt the Tsc1 or Tsc2 gene in a principal cell line and used ultracentrifugation to isolate extracellular vesicles. Conditioned media or isolated extracellular vesicles were used in cell culture studies with M1 intercalated cell line as a target. We measured the phosphorylation of S6 expression as a read out.


Both animals develop renal cystic disease, by far more prominently in the renal cortex, and the cysts highly expressed pS6. Cystic epithelium was predominantly type A intercalated cells, and principal cells seemed to drop out with time in the Aqp2CreTsc2 renal cysts. The cysts in both animals continued to express tuberin and hamartin, and we noted extracellular vesicles in some of the smaller cyst lumens of perfused animals. Using a tissue culture model we found that principal cell extracellular vesicles activated intercalated cell mTORC1 activity, and this was exaggerated if either the Tsc1 or Tsc2 gene was disrupted.


We demonstrate that mice with principal cell specific Tsc2 inactivation and mice with renal pericyte Tsc1 inactivation develop cortical cystic disease comprised of type A intercalated cells. The cystic epithelium appears to have an activated mTORC1 axis, though still express hamartin and tuberin. Cell culture experiments suggest a role for extracellular vesicles in this growth activation signal.


  • Other U.S. Government Support