Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

Abstract

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

“…The TSC cystic disease can manifest as one or more of at least five patterns of disease [1], and appears to have a very novel cystogenic mechanism involving the renal tubular cells [14]. In a previous study, we reported that the loss of Tsc2 gene in a mouse renal principal cell affected the phenotype of intercalated cell causing an enhanced mTORC1 activity, thus leading to renal cystogenesis likely via an EV-dependent pathway [14] ( Figure 5). To elucidate our hypothesis, we utilized a well characterized in vitro model.…”

“…The majority of TSC patient develop some form of kidney cyst during their life time but the exact mechanism of kidney cystogenesis in tuberous sclerosis complex is unknown [20]. The TSC cystic disease can manifest as one or more of at least five patterns of disease [1], and appears to have a very novel cystogenic mechanism involving the renal tubular cells [14]. In a previous study, we reported that the loss of Tsc2 gene in a mouse renal principal cell affected the phenotype of intercalated cell causing an enhanced mTORC1 activity, thus leading to renal cystogenesis likely via an EV-dependent pathway [14] ( Figure 5).…”

“…In this model, disease then is caused by dysregulated tissue repair rather than deregulated cellular proliferation. This would account for why cells with an intact TSC axis are involved in the disease phenotype [14].…”

“…These intercalated cells maintained the Tsc2 locus and exhibited increased mTORC1 activity [14]. The mechanism of phenotype spreading between Tsc2-null cells and intact cell is mediated by extracellular vesicles (EVs) [14]. This phenotype spreading model was also demonstrated in neuronal cells of tuberous sclerosis [15].…”

“…In a mouse model that exhibited a specifically targeted deletion of Tsc2 in the principal cells by using the aquaporin-2 promoter to drive the expression of Cre-recombinase, we found that cysts were composed almost entirely of intercalated cells [14]. These intercalated cells maintained the Tsc2 locus and exhibited increased mTORC1 activity [14]. The mechanism of phenotype spreading between Tsc2-null cells and intact cell is mediated by extracellular vesicles (EVs) [14].…”