Significant reduction of renal mass results in proteinuria, glomerulosclerosis and tubulo-interstitial injury culminating in end-stage chronic renal failure (CRF). Accumulation of lipids in the kidney can cause renal disease. Uptake of oxidized lipoproteins via scavenger receptors, reabsorption of filtered protein-bound lipids via megalin-cubilin complex and increased glucose load per nephron can promote lipid accumulation in glomerular, tubular and interstitial cells in CRF. Cellular lipid homeostasis is regulated by lipid influx, synthesis, catabolism and efflux. We examined lipid-regulatory factors in the remnant kidney of rats 11 weeks after 5/6 nephrectomy (CRF) or sham operation. CRF resulted in azotemia, proteinuria, lipid accumulation in the kidney, up-regulation of megalin, cubilin, mediators of lipid influx (scavenger receptor class A; SR-A1, and lectin-like oxidized receptor-1; LOX-1), lipid efflux (liver X receptor-/; LXR-/, ATP-binding cassette transporter; ABCA1),and fatty acid biosynthesis (carbohydrate response element binding protein; ChREBP, fatty acid synthase; FAS and acetyl-CoA carboxylase; ACC). However, factors involved in cholesterol biosynthesis (sterol regulatory element binding protein; SREBP-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HMG-CoA reductase, SCAP, Insig-1 & Insig-2) and fatty acid oxidation (peroxisome proliferator-activated receptor; PPAR-, acyl-CoA oxidase; ACO, and liver-type fatty acid binding protein; L-FABP) were reduced in the remnant kidney. Thus CRF results in heavy lipid accumulation in the remnant kidney which is mediated by upregulation of pathways involved in tubular reabsorption of filtered protein-bound lipids, influx of oxidized lipoproteins and synthesis of fatty acids and downregulation of pathways involved in fatty acid catabolism.