Tsc2 mutation induces renal tubular cell nonautonomous disease

Prashant Kumar, Fahad Zadjali, Ying Yao, Daniel Johnson, Brian Siroky, Aristotelis Astrinidis, Peter Vogel, Kenneth W Gross, John J Bissler

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

TSC renal cystic disease is poorly understood and has no approved treatment. In a new principal cell-targeted murine model of Tsc cystic disease, the renal cystic epithelium is mostly composed of type A intercalated cells with an intact Tsc2 gene confirmed by sequencing, although these cells exhibit a Tsc-mutant disease phenotype. We used a newly derived targeted murine model in lineage tracing and extracellular vesicle (EV) characterization experiments and a cell culture model in EV characterization and cellular induction experiments to understand TSC cystogenesis. Using lineage tracing experiments, we found principal cells undergo clonal expansion but contribute very few cells to the cyst. We determined that cystic kidneys contain more interstitial EVs than noncystic kidneys, excrete fewer EVs in urine, and contain EVs in cyst fluid. Moreover, the loss of the Tsc2 gene in EV-producing cells greatly changes the effect of EVs on renal tubular epithelium, such that the epithelium develops increased secretory and proliferative pathway activity. We demonstate that the mTORC1 pathway activity is independent form the EV production, and that the EV effects for a single cell line can vary significantly. TSC cystogenesis involves significant contribution from genetically intact cells conscripted to the mutant phenotype by mutant cell derived EVs.

Original languageEnglish
JournalGenes Diseases
DOIs
Publication statusPublished - 2021
Externally publishedYes

Keywords

  • Cell nonautonomous trait
  • Polycystic kidney disease
  • Renalcystogenesis
  • Tuberous sclerosis complex

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics(clinical)
  • Cell Biology

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