Abstract
Background/Aims: Inflammation is an unavoidable milieu for renal tubular cells during the development of renal tubulointerstitial fibrosis. It has been demonstrated that chemokines including monocyte chemoattractant protein-1 (MCP-1) and IL-8 are related to tubulointerstitial lesions. 15d-PGJ<sub>2</sub> may modulate renal tubulointerstitial fibrosis progression via anti-inflammatory effects. However, no information is known about the effects of 15d-PGJ<sub>2</sub> on chemokine expression in human proximal renal tubular cells (HPTECs) under inflammation. Methods: In the present study, HPTECs (HK-2 cells) were stimulated with lipopolysaccharide (LPS) only, or preincubated with 15d-PGJ<sub>2</sub>. IL-8 and MCP-1 expressions were determined by real-time PCR and ELISA. Nuclear factor-γB (NF-γB) location was detected by immunofluorescence analysis. The p-IKK, p-IγBa and p65/p50 were analyzed by immunoblotting. To investigate the mechanism of inhibitory effects of 15d-PGJ<sub>2</sub>, the PPAR-γ gene was effectively silenced in HK-2 cells using specific siRNA. Results: The results showed that application of LPS significantly increased IL-8 and MCP-1 production. Phosphorylation of IγBa, IKK and nucleus translocation of NF-γB significantly increased in LPS-stimulated HK-2 cells. 15d-PGJ<sub>2</sub> downregulated LPS-induced IL-8 and MCP-1 production. Interestingly, in PPAR-γ-deficient HK-2 cells, 15d-PGJ<sub>2</sub> was still capable of inhibiting chemokines expression and attenuating phosphorylation of IγBa and nucleus translocation of NF-γB. Conclusion: Collectively, these results suggest that 15d-PGJ<sub>2</sub> exerts anti-inflammatory actions on HK-2 cells by attenuating chemokines expression. 15d-PGJ<sub>2</sub> inhibits chemokines expression via a PPAR-γ-independent way, which is related to block NF-γB pathway. Since NF-γB is an important regulator of the response of HPTECs to injury, PPAR-γ agonists may represent a key pharmacological target for ameliorating inflammation-associated tubulointerstitial fibrosis.
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