Tuberous sclerosis complex exhibits a new renal cystogenic mechanism.

John J Bissler,Michael E Rusiniak,Kamyar Zahedi,Yanqing Wang,Kenneth W Gross,Heinz Baumann,Dave Bridges,Joel T Finley,Fahad Zadjali,Ying Yao,Brian J Siroky,Jeanna R Redd,Aristotelis Astrinidis,Sharon Barone,Manoocher Soleimani

doi:10.14814/phy2.13983

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.

Highlights

Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 genes and affects over one million patients world-wide (Ewalt et al 1998; Dabora et al 2001; Rakowski et al 2006)
We report a new cellular cross-talk mechanism resulting in tuberous sclerosis renal cystogenesis
A fundamental feature of this mechanism involves a small population of Tsc-mutant renal principal epithelial cells or pericytes that induce or reprogram genetically normal A-intercalated cells to upregulate their mechanistic target of rapamycin complex 1 (mTORC1) activity, proliferate, and form renal cysts (Fig. 10)

Summary

Introduction

Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 genes and affects over one million patients world-wide (Ewalt et al 1998; Dabora et al 2001; Rakowski et al 2006). Renal cystic disease is detected by MRI in ~50% of TSC patients, the pathogenesis is not well studied. Premature decline of glomerular filtration rate (GFR) occurs in ~40% of patients with TSC (Bissler and Kingswood 2016) and can occur in the absence of overt angiomyolipomata bleeding or interventions and is, at least in part, due to renal cystic disease. TSC renal cystic disease exhibits five distinct patterns (Bissler 2018; Bissler and Kingswood 2018) and involves the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. The TSC proteins directly regulate mTORC1 activity and influence downstream processes, including renal development, homeostasis, and malignancy. The TSC proteins play a pivotal role in cell biology, how their regulation of the mTORC1 pathway is involved in cystogenesis is not known

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Conclusion