Interleukin-17A induces renal fibrosis through the ERK and Smad signaling pathways

Abstract

Interleukin (IL)-17A is upregulated in several renal diseases and plays a crucial role in renal inflammation. However, it remains unclear how IL-17A contributes to renal fibrosis. Our result demonstrated that IL-17A expression was upregulated in the obstructed kidney of unilateral ureter obstruction (UUO) mice when compared to the contralateral control kidney. Inhibition of IL-17A functions by the intravenous administration of an anti-IL-17A receptor antibody (100 μg) 2 h prior to UUO and on post-UUO day 1 and 3 significantly reduced fibronectin expression in the UUO kidney. The addition of IL-17A (25-100 μg) to human renal proximal tubular cells or renal fibroblasts caused an increase in fibronectin production and extracellular signal-regulated kinase (ERK)1/2 activation, which were reduced upon pretreatment with the ERK inhibitor U0126. The level of phosphorylated (p)-ERK1/2 was increased in the UUO kidney, but reduced by the administration of the anti-IL-17A receptor antibody, verifying the importance of the ERK pathway in vivo. TGF-β1 mRNA expression and protein were increased in the UUO kidney and in IL-17A-stimulated cultured cells. The administration of an anti-TGF-β1 neutralizing antibody or TGF-β1 receptor I inhibitor (SB431542) to cells abrogated the IL-17A-mediated increase of fibronectin production. IL-17A induced an increase in p-Smad2 and p-Smad3 expression at 7.5 min and 24 h and pretreatment with the anti-TGF-β1 neutralizing antibody, and SB431542 reduced the IL-17A-stimulated increase of p-Smad2. Knockdown of Smad2 or Smad3 expression inhibited the IL-17A-enhanced production of fibronectin. These results suggest an essential role for the TGF-β/Smad pathway in the IL-17A-mediated increase of fibronectin production. This study demonstrates that IL-17A contributes to the production of extracellular matrix, and targeting its associated signaling pathways could provide a therapeutic target for preventing renal fibrosis.

Keywords: ERK; Fibrosis; IL-17A; Kidney; Smad.