Renal cystic disease in tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is associated with TSC1 or TSC2 gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.

Keywords: Tuberous sclerosis complex; cell nonautonomous trait; extracellular vesicles; renal cysts.

Figure 1.

Role of EVs in renal cystogenesis. (a) Role of EVs in the initiation, promotion, and progression of TSC renal cystic disease. The cystogenic process is initiated (labeled with the white “1” in the red background) by the loss of a Tsc locus in the tubule. This genetic change results in increased EV production with different cargo. These EVs are taken up by renal tubule cells with intact TSC genes or by kidney resident macrophages. These EVs cause an increase in the mTORC1 axis and promote cystogenesis (labeled as “2”). The increase in the recipient cell mTORC1 axis is through two mechanisms. The first one (labeled as 2a) is mediated by the EV RNA cargo (miRNA and lncRNA) altering transcription in genetically intact cells, and the other mechanism involves mTORC1 activation down-stream from toll-like receptors 7 and 8 activation by the double-stranded miRNA (2b). The lesion undergoes progression (labeled as “3”) by similar mechanisms because this genetically intact cell now (labeled 3A) increases production of EVs similar to cells that have lost their TSC gene function and have an increased mTORC1 activity. This TLR activation also increases cytokine production (e.g. IL-6) which induces down-stream mTORC1 activation (labeled 3B) in adjacent cells. (b) Flow diagram of the signaling amplification network. The EVs from the mutant cells initiate a potentially pathological amplification of mTORC1 activity that drives additional miRNA and EV production that further feedback to activate the system through reprograming non-mutant cells and activating proliferation signals through TLR7 and 8 and signaling through cytokine receptors to also drive mTORC1 activity.