Kidney fibrosis is the final common pathway of all chronic kidney diseases but there is no approved drug to treat kidney fibrosis in the United States. There is general agreement that myofibroblasts are the cell type responsible for scar formation in fibrotic kidney disease, and ablating these cells improves kidney function in experimental models. However, there is very little information regarding small molecules that might alter myofibroblast function and reduce scar. Here we propose to dissect the ability of retinoic acid and its precursors to ameliorate kidney fibrosis as a foundation for establishing a new treatment paradigm. Our preliminary data indicates that retinoids inhibit myofibroblast function, and we will validate this observation using complementary strategies in vitro and in vivo. The data generated will establish a clear path towards translation of a new therapy to prevent kidney fibrosis by targeting retinoic acid signaling in myofibroblasts.
Kidney fibrosis is the leading cause of kidney failure worldwide, and represents an enormous health burden. We propose to understand how retinoic acid, a derivative of vitamin A, blocks kidney fibrosis in experimental models. We hypothesize that treatment with a retinoic acid precursor will block fibrosis, but without the toxic effects associated with giving patients retinoic acid itself. With this information, we will be in positionto validate retinoid-based treatment strategies to prevent kidney fibrosis from progressing to end stage kidney disease.
|Kramann, Rafael; Schneider, Rebekka K; DiRocco, Derek P et al. (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16:51-66|
|Kramann, Rafael; Humphreys, Benjamin D (2014) Kidney pericytes: roles in regeneration and fibrosis. Semin Nephrol 34:374-83|