Inactivation of Tsc2 in Abcg2 Lineage Derived Cells Drives the Appearance of Polycystic Lesions and Fibrosis in the Adult Kidney.

Inactivation of Tsc2 in Abcg2 Lineage Derived Cells Drives the Appearance of Polycystic Lesions and Fibrosis in the Adult Kidney. Am J Physiol Renal Physiol. 2019 Aug 28;: Authors: Gewin L, Summers ME, Harral JW, Gaskill CF, Nlandu Khodo S, Neelisetty S, Sullivan TM, Hopp K, Reese JJ, Klemm DJ, Kon V, Ess KC, Shi W, Majka SM Abstract 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 Tsc2 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 Tsc2 knockdown in the ATP binding cassette G2 (Abcg2) expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated Tsc2, lacking exons 36-37 with an intact 3 prime region and Pkd1, is driven by Abcg2. Here we demonstrate that selective expression of Tsc2fl36-37in the Abcg2pos 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 Tsc2 function in the...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research