Over 30M people in the U.S. suffer from diabetes; one-third have CKD and almost half of incident ESRD is due to diabetic kidney disease (DKD). Albuminuria and decreased GFR reflect glomerular dysfunction, and are risks for DKD progression. However, tubular atrophy is superior to glomerular pathology as a predictor of DKD progression. The mechanisms for loss of tubular epithelial cells have not been established. Non-esterified fatty acids (NEFA) circulate bound to albumin, or as triglycerides. Neither is filtered due to their size. Low concentrations of filtered NEFA are reabsorbed by apical scavenger transporters in the proximal tubule. This segment normally uses NEFA as metabolic substrates that are taken up across the basolateral membrane. In DKD, injured glomeruli permit filtration of albumin-bound NEFA in large quantities, which are then reabsorbed by apical proximal tubule transporters, causing accumulation of NEFA, long-chain acyl-CoAs, and apoptosis. Apical NEFA uptake is mediated primarily by fatty acid transport protein-2 (FATP2), and at NEFA concentrations that mimic DKD in vitro, is cytotoxic. Basolateral NEFA uptake is FATP2-independent and not cytotoxic. We showed that global FATP2 deletion in genetic and inducible mouse models of DKD improves GFR, tubular atrophy and plasma glucose, but the mechanisms are not understood. First, FATP2 deletion does not completely block AP proximal tubule NEFA uptake. Second, how FATP2 deletion account for the enhanced synthesis and decreased degradation of NEFA associated with DKD, has not been reconciled. In DKD proximal tubules accumulate lipid droplets (LD), which store excess NEFA to prevent lipotoxicity. Perilipin (Plin) proteins facilitate LD assembly and maintenance. Plin5 augments LD docking with mitochondria, thereby enhancing autophagy, reducing ER stress and apoptosis, and shifts metabolism from -oxidation to lipid storage and glucose utilization. Our data show that proximal tubule Plin5 expression is blunted in DKD, and increased with FATP2 deletion. Plin5 overexpression inhibited, and Plin5 loss of function exacerbated lipoapoptosis. These data suggest that the beneficial effect of FATP2 deletion is partly due to enhanced expression of Plin5. We also propose that Plin5 mediates metabolic reprogramming from -oxidation to glycolysis and decreased gluconeogenesis, which would mediate the hypoglycemic effects of FATP2 deletion. Hypothesis: In DKD-associated glomerular injury, constitutive basolateral NEFA transport, combined with apical FATP2-regulated proximal tubule NEFA uptake leads to lipotoxicity, tubular atrophy and progressive DKD. Tubular atrophy can be circumvented by proximal tubule FATP2 deletion or enhanced Plin5-dependent lipid droplet expansion. The hypothesis will be pursued with the following specific aims: 1. To determine whether proximal tubule FATP2 mediates lipotoxicity and DKD progression. 2. To determine the role of Plin5 in proximal tubule metabolism and DKD. 3. To...