Statins but not thiazolidinediones attenuate albumin-mediated chemokine production by proximal tubular cells independently of endocytosis.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Chana
Ravinder S
RS
Department of Infection, Faculty of Medicine and Biological Sciences, University of Leicester, Leicester, UK.
Sidaway
James E
JE
Brunskill
Nigel J
NJ
D000418:Albumins / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D004705:Endocytosis / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011507:Proteinuria / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D000418:Albumins; D018946:Chemokine CCL5; D018925:Chemokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D045162:Thiazolidinediones; D012710:Serum Albumin, Bovine; C037112:9-deoxy-delta-9-prostaglandin D2; C089946:2,4-thiazolidinedione; C002963:geranylgeranyl pyrophosphate; D015230:Prostaglandin D2; D008798:Mevalonic Acid