geranylgeranyl-pyrophosphate and 2-4-thiazolidinedione

Proximal tubular epithelial cells (PTEC) secrete chemokines under proteinuric conditions. Both statins and thiazolidinediones (TZDs) possess pleiotropic anti-inflammatory effects. This study examined the ability of statins and TZDs and the natural peroxisome proliferator activated receptor-gamma (PPARgamma) agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) to attenuate the proteinuria-induced pro-inflammatory phenotype of PTEC.. Mouse PTEC were treated with statins, TZDs and PGJ(2 )and effects on uptake and binding of FITC-albumin determined. PTEC were incubated with fatty acid free bovine serum albumin with or without statins/TZDs/PGJ(2), and the release of MCP-1 and RANTES measured.. Statins and TZDs significantly inhibited PTEC albumin endocytosis. PGJ(2 )had no effect. Incubation of PTEC with albumin significantly stimulated production of MCP-1 and RANTES. Co-treatment with statins and PGJ(2) significantly reduced albumin-stimulated chemokine production, an effect reversed by the addition of mevalonate and geranylgeranyl pyrophosphate. In contrast, TZDs had no effect on albumin-mediated chemokine production.. Statins and PGJ(2), but not TZDs, prevent the development of a PTEC pro-inflammatory phenotype in response to albumin. Albumin endocytosis is not a prerequisite for PTEC chemokine production, and inhibition of albumin endocytosis alone is insufficient to attenuate chemokine production. These studies suggest a therapeutic role for statins and some PPARgamma ligands in proteinuric renal disease.

Topics: Albumins; Animals; Cells, Cultured; Chemokine CCL5; Chemokines; Endocytosis; Epithelial Cells; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Tubules, Proximal; Mevalonic Acid; Mice; Mice, Inbred C57BL; Polyisoprenyl Phosphates; Prostaglandin D2; Proteinuria; Serum Albumin, Bovine; Thiazolidinediones