Changes in proximal tubule gene expression leads to cystogenesis and tubular damage in Tuberous sclerosis

Tuberous sclerosis (TS) is a genetic disorder caused by inactivating mutations in either the Tsc1 or Tsc2 genes. These mutations induce mTOR activation resulting in cell growth and tumorigenesis. The renal presentation of TS includes renal angiomyolipoma and cystic disease and is associated with high mortality. The exact molecular mechanisms leading to the tubular cell damage and cyst formation remains poorly understood. To this end, we developed a mouse model where Tsc1 was deleted in nephron progenitor cells (NPCs). We show that Tsc1 knockout in NPCs lead to a lethal phenotype of severe renal cystic disease. The tubular damage were visible already at E15.5, and were associated with an increased proliferation marker ki67, c-Myc overexpression and elevated mTOR pathway activation. mTOR inhibition by rapamycin injection throughout pregnancy prevented tubular damage and cyst formation and prolonged offspring life span from P2 to P14 days. Rapamycin also prevented the increase in tubular proliferation marker and c-Myc overexpression. Gene expression profiling of isolated proximal tubule cells from control, Tsc1 KO mice and Tsc1 KO mice subjected to rapamycin treatment, identified specific target genes and pathways that have the potential to contribute to the tubular cell damage and cytogenesis. Among these pathways, the inflammatory response seems to be highly elevated in Tsc1 KO mice, and its inhibition by dexamethasone injection throughout pregnancy, prevented cyst formation in Tsc1 KO offspring with ought affecting tubular damage.

Our results clearly demonstrate the contribution of the inflammatory response in the kidney manifestation of Tuberous sclerosis.