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Sources of Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM088129. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflict of Interests exist for the authors.

Introduction

Acquired renal cystic disease (ARCD) imparts a high risk for renal cell carcinoma (8%) in patients with end-stage renal disease. The molecular mechanism of cyst formation in ARCD remains unknown, although increased hepatocyte growth factor / C-MET signaling have been implicated in cyst formation. To explore molecular mechanisms of renal cyst development relevant to ARCD, we developed a murine model system based on tissue-selectable C-Met activation and transposon-mediated mutagenesis.

Methods

To allow conditional activation of C-Met signaling, we engineered a tandem duplicated and mutated human C-MET coding sequence. Cre recombinase catalyzes exchange of the wild type C-Met locus with a constitutively active variant (M1248T). C-met^+/M1248T mice were crossed with mice carrying the mutagenic Sleeping Beauty (Onc2) transposable element activated by a cre-dependent transposase (trpase). Localization to the renal epithelium was achieved by ggt-cre. Mice with activated C-Met and transposon mutagenesis (1: c-met^+/M1248T; Onc2^+/-, trpase^+/-; ggt-cre^+/-) were compared to mice with activated C-Met (2: c-met^+/M1248T; ggt-cre^+/-) or activated transposon mutagenesis (3: Onc2^+/-, trpase^+/-; ggt-cre^+/-) alone. Mice were serial imaged by ultrasound and MRI. All kidneys were then examined grossly and histologically at necropsy after aging.

Results

All mice (N=5) with both C-Met hyperactivation and transposon activity (1) developed large renal cysts by 6 months. No mice with only C-Met hyper-activation (2; N=10) or transposon activity (3; N=10) developed cysts by 6 months. Histological analysis demonstrated fluid filled and hemorrhagic renal cysts without evidence for malignancy.

Conclusions

C-Met hyperactivation is insufficient to drive renal cyst formation in isolation. Combining M1248T with transposon mutagenesis drove renal cyst formation with 100% penetrance. By mapping transposon insertion sites in cyst-lining epithelial cells in this model, we can now begin to isolate these interacting genes, which may improve our understanding of the molecular mechanisms underlying ARCD.

Funding

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM088129. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflict of Interests exist for the authors.