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Department of Cell Physiology and Pharmacology, and *Department of Nephrology, University of Leicester, Faculty of Medicine and Biological Sciences, Leicester, England.
Correspondence to Dr. Nigel John Brunskill, Department of Cell Physiology and Pharmacology, University of Leicester, Faculty of Medicine and Biological Sciences, Medical Sciences Building, University Road, PO Box 138, Leicester, LE1 9HN, England. Phone: 44-116-258-8043; Fax: 44-116-252-5045;
ABSTRACT. In nephrotic syndrome, large quantities of albumin enter the kidney tubule. This albumin carries with it a heavy load of fatty acids to which the proximal tubule cells are exposed at high concentration. It is postulated that exposure to fatty acids in this way is injurious to proximal tubule cells. This study has examined the ability of fatty acids to interact with peroxisome proliferator–activated receptors (PPAR) in primary cultures of human proximal tubule cells. Luciferase reporter assays in transiently transfected human proximal tubule cells were used to show that albumin bound fatty acids and other agonists activate PPAR
in a dose-dependent manner. One of the consequences of this activation is apoptosis of the cells as determined by changes in cell morphology, evidence of PARP cleavage, and appearance of DNA laddering. Overexpression of PPAR in these cells also results in enhanced apoptosis. Both fatty acid–induced PPAR activation and apoptosis in these cells can be blocked by PPAR response element decoy oligonucleotides. Activation of PPAR by the specific agonist PGJ2 is associated with inhibition of cell proliferation, whereas activation by albumin bound fatty acids is accompanied by increased proliferation. However, the net balance of apoptosis/proliferation favors deletion of cells. These results implicate albumin-bound fatty acids as important mediators of tubular injury in nephrosis and provide fresh impetus for pursuit of lipid-lowering strategies in proteinuric renal disease. E-mail: njb18@le.ac.uk
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