NDT Advance Access published online on January 20, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn746
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Protective effect of peroxisome proliferator-activated receptor-gamma agonists on activated renal proximal tubular epithelial cells in IgA nephropathy
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
Correspondence and offprint requests to: Kar Neng Lai, Department of Medicine, Room 411, Professorial Block, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Tel: +852-28554251; Fax: +852-28162863; E-mail: knlai{at}hkucc.hku.hk
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Abstract |
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Background. We have previously demonstrated a glomerulo-tubular ‘crosstalk’ operating in the pathogenesis of tubulointerstitial injury in IgA nephropathy (IgAN). The present study aims to explore any possible beneficial effect of a peroxisome proliferator-activated receptor-
(PPAR-) agonist in alleviating the tubulointerstitial inflammation in IgAN.
Methods. Human proximal tubular epithelial cells (PTEC) were pre-treated with increasing concentration of a PPAR- agonist rosiglitazone or troglitazone (0–5 µM) followed by further incubation with the conditioned medium (IgA-HMC) collected from human mesangial cells (HMC) incubated with polymeric IgA isolated from IgAN patients. Gene expression of interleukin-6 (IL-6) and angiotensin II type 1 receptor (ATR1) was detected by reverse transcription–polymerase chain reaction (RT–PCR); protein expression of IL-6 and ATR1 was determined by ELISA and western blot, respectively. The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) activation was examined by western blot.
Results. An IgA-HMC conditioned medium prepared from IgAN patients increased gene expression and protein synthesis of IL-6 and ATR1 in PTEC when compared with a conditioned medium prepared from healthy controls. The upregulated gene expression and protein synthesis of IL-6 and ATR1 in PTEC induced by the IgA-HMC conditioned medium were readily attenuated following pre-treatment with a PPAR- agonist, thiazolidinedione (TZD). The ATR1-downregulating effect exerted by the PPAR- agonist occurred through the inhibition of ERK1/2 activation. The PPAR- antagonist, GW9662, significantly attenuated the inhibitory action of rosiglitazone on the increased synthesis of IL-6 and ATR1 protein.
Conclusion. Our current findings suggest that the PPAR- agonist attenuates excessive inflammatory response in activated PTEC in IgAN through suppressing ATR1 expression. This ATR1-downregulating effect is likely through the inhibition of ERK1/2 activation and is found to be PPAR- dependent. TZDs may possibly be new therapeutic additives to established treatment regime for renin–angiotensin system (RAS) blockade in IgAN.
Keywords: angiotensin II type 1 receptor; IgA nephropathy; PPAR-gamma agonist; tubulointerstitial injury; tubular epithelial cells
Received for publication: 12. 7.08
Accepted in revised form: 12.12.08