Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease - PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease. The goal of this study is to determine if renal interstitial myofibroblasts play an essential role in ADPKD progression by undergoing autophagy and supplying nutrients that support cyst growth. While myofibroblasts are known to be important for renal fibrosis, our novel preliminary data suggests that myofibroblasts could directly regulate cyst growth in ADPKD kidneys by paracrine mechanisms. We found that secreted factors from cyst epithelial cells such as lactate, stimulate autophagy in myofibroblasts by a hypoxia-inducible factor (HIF1α)- dependent mechanism. Moreover, factors such as glutamine, secreted by ADPKD renal myofibroblast- by a HIF1α and autophagy dependent mechanism increased proliferation and cyst growth of human ADPKD cyst epithelial cells. Hence, we hypothesize that, cyst epithelial cells use paracrine mechanisms to induce autophagy in myofibroblasts, leading to secretion of cyst-growth promoting factors. Aim 1 will test if reducing the renal myofibroblast population will reduce cyst growth in mouse ADPKD kidneys. Aim 2 will determine the role of myofibroblast-specific HIF1α in cyst growth. In Aim 3, the role of myofibroblast-specific autophagy and metabolites secreted by myofibroblasts in cyst-expansion will be examined. In addition to the innovative hypothesis, our studies will use state of the art transgenic and tissue specific gene knockout mice and identify myofibroblast -specific secreted factors, important for regulation of cyst growth in ADPKD kidneys. These studies are significant because we test a novel and fundamental mechanism by which cyst epithelial cells manipulate myofibroblasts in their microenvironment to produce nutrients to support cyst growth and disease progression in ADPKD. Although altered metabolism, hypoxia, autophagy, and the role of the cyst microenvironment in cyst growth are emerging fields in ADPKD pathophysiology, the importance of myofibroblast-mediated regulation of cyst growth is unclear. This study will build on our lab's strengths in studying ADPKD pathophysiology, with co-investigators and collaborators who are leaders in the fields of PKD, hypoxia, metabolism or autophagy. The results are expected to lead to development of better therapies for ADPKD.
