Mechanisms of renal lipotoxicity - chronic kidney disease (CKD) is characterized by progressive kidney damage and inability to function

CKD is currently the leading cause of end stage renal failure, contributing to a growing public health burden. Excess lipids in the form of free fatty acids (FFA) promote development of tubulointerstitial fibrosis and cellular apoptosis suggesting that lipotoxicity, the excess accumulation of lipids in non-adipose tissues, contributes to the progression of disease. Despite this large public health burden, dialysis and kidney transplant are the only current treatments for chronic kidney disease. Therefore, my goal is to uncover underlying cellular mechanisms that contribute to the effects of FFA induced lipotoxicity in kidney tubular epithelial cells and to the development of CKD, the completion of which may lead to the discovery of new therapeutic targets or treatments. The greka lab has expertise in kidney biology and high-throughput screening technologies, which provides an exceptional environment for me to investigate this problem during my PHD to enhance my cell and molecular biology skill set as well as my knowledge of lipid and renal biology. Demonstrative of the greka lab's aptitude to approach this problem, they had previously identified FAS-associated factor 2 (FAF2) knockout (KO), using an unbiased genome-wide screen, as a top protective HIT of palmitate (PA) induced lipotoxicity. Although the role of FAF2 in lipotoxicity and kidney biology is unknown. In completion of the proposed fellowship, i intend to describe the mechanism by which FAF2 KO is protective of PA induced lipotoxicity. I will explore this by identifying the mechanism by which FAF2 KO is protective of palmitate-induced toxicity (aim 1) and investigating the consequences of FAF2 KO in murine renal proximal tubule cells (aim 2). Upon completion of these aims i expect to identify new mechanisms of lipotoxicity in kidney epithelial cells that may elucidate a new therapeutic strategy for treatment of CKD. I will describe how FAF2 and other key mediators of lipotoxicity modulate the handling of saturated lipids, such as palmitate, and the processes that contribute to decreased cell viability in the presence of saturated lipids. I will further evaluate the effects of FAF2 KO in mouse renal proximal tubule cells by examining changes in kidney function and protection from high-FAT diet induced damage. Elucidation of these processes will provide insight to the underlying mechanisms that contribute to FFA induced lipotoxicity in the kidney and may reveal new targets for CKD related therapeutics.