Dissecting the molecular mechanisms underlying lipotoxicity in the kidney.

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Abstract Chronic kidney diseases affect millions around the world. A combination of genetic and environmental factors can contribute to the progression of kidney disease. Obesity is a risk factor for metabolic diseases like type 2 diabetes (T2D), which has been highly associated with kidney disease progression. T2D is often characterized by high levels of lipids in the bloodstream, which can be toxic to non-adipose tissues like the kidney. The consequent lipotoxicity may injure kidney cells, contributing to the pathogenesis of diseases like diabetic nephropathy, but the specific cellular effects of lipotoxicity in the kidney are unknown. The first aim will identify which FFAs are lipotoxic to kidney tubular epithelial cells and what cellular stress responses they induce, using readout methods like ER stress, cell viability, and transcriptomics. The second aim will use Perturb-Seq, which combines CRISPR screens with single-cell RNA sequencing, to identify genes whose perturbations induce transcriptional signatures of cellular stress states, followed by validation in kidney organoids. Ultimately, these experiments will reveal the genes and pathways that mediate FFA-induced lipotoxic injury in kidney cells. Given the largely unmet need for kidney disease therapies, our study will provide a step towards revealing new targets as well as expanding our knowledge on the fundamental mechanisms underlying kidney disease.