Abstract
Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex (TSC) disease. The mechanisms underlying TSC cystic kidney disease remain unclear, with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1-null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1-null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1-null kidneys. Dexamethasone administration during pregnancy decreased cyst formation by not only inhibiting the inflammatory response, but also interfering with the mTORC1 pathway. These results reveal mechanisms of cystogenesis in TSC disease and suggest interventions before birth to ameliorate cystic disease in offspring.
Highlights
Tuberous sclerosis complex disease (TSC) is a genetic disorder affecting various organs, including the brain, kidney, skin, and heart, with an estimated prevalence of approximately 1:6,000 in all populations studied [1,2,3,4]
We have previously shown that complete deletion of TSC1 in nephron progenitor cells (NPCs) induces tubular damage as early as E15.5 with swollen cellular appearance and occluded lumen
The increased protein S6 (pS6) staining initially appeared in the injured tubular cells and in the cyst-lining epithelial cells, which originate from the proximal tubular cells (PTCs)
Summary
Tuberous sclerosis complex disease (TSC) is a genetic disorder affecting various organs, including the brain, kidney, skin, and heart, with an estimated prevalence of approximately 1:6,000 in all populations studied [1,2,3,4]. The complex acts as a tumor suppressor and inhibits the activity of mTOR complex 1 (mTORC1), a central regulator of various cellular functions such as protein translation, proliferation, metabolism, and autophagy [5,6,7]. The hamartin–tuberin complex has mTORC1-independent cellular effects through distinct pathways. We have previously shown that the effect of improved nephron endowment by TSC1 hemizygous deletion in nephron progenitor cells (NPCs) is independent of mTORC1 activity [8, 9]. Interruption of the hamartin–tuberin complex by TSC2 deletion has mTORC1-independent effects on prostaglandin production and NOTCH activity [10,11,12]. In cancer cells, TSC2 was shown to regulate VEGF gene expression in a mTOR-independent pathway [15]. Some of the clinical manifestations of TSC disease respond only partially to mTOR inhibitors [2, 13, 14, 16, 17]
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