Tuberous sclerosis complex 2, or Tuberin, is a pivotal regulator of the mechanistic target of rapamycin (mTOR) signaling pathway that controls cell survival, proliferation, growth and migration. Loss of function manifests in organ specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of kidney identified Abcg2 expression in renal proximal tubules of adult mice as well as a novel cell population. The impact in adult kidney of knockdown in the ATP binding cassette G2 (Abcg2) expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated , lacking exons 36-37 with an intact 3 prime region and Pkd1, is driven by Here we demonstrate that selective expression of in the Abcg2 lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells which results in progressive proximal tubule injury, impaired kidney function, the formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of function in the Abcg2 expressing proximal tubule epithelium and mesenchyme during development of cystic lesions and remodeling of kidney parenchyma.