Introduction: Chronic Kidney Disease (CKD) affects 10-15% of the world population, and 30-40 million people in the United States alone. Medicare costs for patients with CKD in 2017 were $84 billion. There are no effective medications available to treat renal fibrosis, which leads to CKD. Current renal replacement therapies, dialysis or transplantation, are costly and are a lifelong detriment to patient quality of life. The goal of this research is to elucidate biochemical pathways involved in the metabolic alterations seen in renal fibrosis in order to identify potential therapeutic target molecules. Methods: Lentiviral infection with TAZ vector and stable selection was used to create HK-2 renal epithelial cells that mimic the TAZ upregulation seen in renal fibrosis. Western blot analysis was then used to identify changes in metabolic enzymes in TAZ overexpressed cells compared to controls. Western blot was also used to analyze the effect of TAZ overexpression on Rac-1 activity, and how the pharmacologic inhibition of Rac-1 with EHT1684 affects TAZ driven metabolic changes. Results: TAZ overexpression in renal epithelial cells leads to upregulation of enzymes involved in the non-reversible steps of glycolysis including Hexokinase, Phosphofructokinase, and Pyruvate Kinase. TAZ overexpression was also associated with increased levels of the constitutively active Rac-1 isoform, Rac-1b. The TAZ driven upregulation of fibrotic markers including Fibronectin, Collagen-1, and CTGF was attenuated by the pharmacologic inhibition of Rac-1 with EHT1684. Rac-1 inhibition with EHT1684 also attenuated TAZ-driven glycolytic reprogramming of renal epithelial cells. Conclusions: Renal tubular TAZ expression promotes fibrotic and glycolytic reprogramming, as well as the activation of Rac. Pharmacological inhibition of Rac expression attenuates glycolytic enzyme expression and fibrotic phenotype. TAZ and Rac may both prove to be novel targets for therapeutic intervention in CKD. SOURCE OF Funding: This research received no specific grant funding.
