Increased Indoleamine 2,3‐dioxygenase expression in the renal fibrogenesis induced by unilateral ureteral obstruction

Abstract

Chronic kidney disease (CKD) is a progressive and high prevalent disease worldwide. Its prevalence doubled on USA on the last decade and as such, deserves attention and a worry to better know its mechanisms.Renal fibrosis is a lead event happening in CKD, and is characterized by an extensive inflammatory process with vast macrophage migration and extracelular matrix accumulation, those leading to damages on the kidney architecture and renal function, and thus worsening the patient condition.In this frame, Indoleamine 2,3‐dioxygenase (IDO), a tryptophan‐catabolizing enzyme with immunomodulatory properties, seems to be deeply associated with mechanisms leading to a bad prognostic to fibrotic and inflammatory conditions. Because IDO may be modulated by Transforming growth factor‐β (TGF‐ β), a key cytokine in the development of renal fibrosis, we hypothesized the relationship between IDO and renal fibrogenesis.In the present study, our objective was to analyze IDO activity and expression in a model of renal fibrogenesis induced by unilateral ureteral obstruction (UUO), and correlate it with markers of epitelial‐mesenchymal transition.Wistar rats were submited to 7 days of UUO. The unobstructed kidneys of the UUO (CL) and the kidneys from SHAM operated rats were used as control. Increased interstitial collagen deposition was remarkable in UUO kidneys. Immunohistochemistry analysis revealed a significant increase in the number of macrophages in UUO kidneys, accompanied by reduction of tubular e‐cadherim expression. Markers of mesenchymal cells (alphaSMA and vimentin) were increased in UUO kidneys, in particular in the renal interstitium and in tubules. These findings characterize the epitelial‐mesenchymal transition process and were accompained by increased TGB‐beta 1 expression (qRT‐PCR). Finally, IDO was markedly expressed in cortical and medular tubules of the UUO kidneys. In addition, IDO activity was accessed from renal tissue, being significantly higher in UUO kidneys. These data demonstrated that IDO is increased during renal fibrogenesis and associated with an increased number of macrophages as well as an upregulation of mesenchymal cell markers, sugesting an association between IDO and EMT.Support or Funding InformationFAPESP (2012/04423‐0)