Activation of tubular epithelial cells in diabetic nephropathy and the role of the peroxisome proliferator-activated receptor-γ agonist

Abstract

The effects of advanced glycation end products (AGE) in the form of glycated albumin (GA) on the proinflammatory phenotype of cultured renal proximal tubular epithelial cells (PTEC) and the therapeutic potential of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist were studied. Human PTEC were exposed to medium alone or supplemented with albumin or GA with or without previous addition of rosiglitazone (0.1 to 0.5 μM). Exposure to GA (up to 0.5 mg/ml) but not the equivalent dose of neat albumin significantly upregulated both mRNA and protein expression of IL-8 and soluble intercellular adhesion molecule-1 (sICAM-1) in a dose- and time-dependent manner. Using immunohistochemistry, ICAM-1 signals were detected in the tubular epithelia and peritubular capillaries in association with AGE deposition and leukocyte infiltration, whereas IL-8 staining was localized in the tubular epithelia of human diabetic kidney biopsies. Also in a dose-dependent manner, GA (0.5 mg/ml) but not albumin caused nuclear translocation of NF-κB and activation of mitogen-activated protein kinase (MAPK) p44/p42 and signal transducer and activator of transcription (STAT-1). Inhibition of these pathways with pyrrolidine dithiocarbamate, PD 98059, and fludarabine, respectively, attenuated GA-induced IL-8 secretion. Rosiglitazone dose-dependently attenuated GA-induced IL-8 and ICAM-1 signals in PTEC and completely abolished GA-induced STAT-1 signals but had no effect on NF-κB and MAPK activation. These findings suggest that AGE stimulate renal tubular expression of adhesion molecule and chemokine that together may account for the transmigration of inflammatory cells into the interstitial space during diabetic tubulopathy. Such proinflammatory phenotype may be partially modified by PPAR-γ ligation through STAT-1 inhibition independent of NF-κB transcriptional activity and MAPK signaling. Copyright © 2006 by the American Society of Nephrology.