Protective effect of peroxisome proliferator-activated receptor-gamma agonists on activated renal proximal tubular epithelial cells in IgA nephropathy

Abstract

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-γ (PPAR-γ) agonist in alleviating the tubulointerstitial inflammation in IgAN.Methods. Human proximal tubular epithelial cells (PTEC) were pre-treated with increasing concentration of a PPAR-γ 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 12 (ERK12) 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-γ agonist, thiazolidinedione (TZD). The ATR1-downregulating effect exerted by the PPAR-γ agonist occurred through the inhibition of ERK12 activation. The PPAR-γ 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-γ agonist attenuates excessive inflammatory response in activated PTEC in IgAN through suppressing ATR1 expression. This ATR1-downregulating effect is likely through the inhibition of ERK12 activation and is found to be PPAR-γ dependent. TZDs may possibly be new therapeutic additives to established treatment regime for renin-angiotensin system (RAS) blockade in IgAN.