BACKGROUND AND PURPOSE: Renal fibrosis represents a common progressive outcome of various kidney injuries, yet no targeted therapies are currently available. Indoleamine-2,3-dioxygenase and its downstream metabolites, kynurenines (KYNs), modulate immune response and may contribute to tissue protection in inflammatory conditions. This study aimed to investigate the potential antifibrotic effects of KYN and kynurenic acid (KYNA). EXPERIMENTAL APPROACH: The effects of KYN and KYNA were investigated in fibroblast culture and in a rat model of unilateral ureteral obstruction-induced renal fibrosis. KEY RESULTS: In vitro, both KYN and KYNA effectively inhibited TGFβ-mediated fibrotic signalling. KYNA suppressed collagen I expression and myofibroblast transdifferentiation. In a rat model of unilateral ureteral obstruction, KYNA reduced fibrotic area, α-SMA-positive regions as well as distal tubular dilatation in cortex and outer medulla. These reno-protective effects were associated primarily with inhibition of the noncanonical TGFβ pathway (pp38, pJNK/JNK) and modulation of the Wnt/β-catenin and JAK2/STAT3 pathways. Furthermore, KYNA influenced proinflammatory NF-κB p65 and shifted the IL-17A/IL-10 axis towards a Treg-dominant profile. KYNA also enhanced fibroblast migration in vitro, suggesting a potential role in promoting wound healing under physiological conditions. CONCLUSION AND IMPLICATIONS: KYNA exerts antifibrotic effects both in vitro and in an in vivo model of renal fibrosis. The mechanisms involve multifaceted modulation of key signalling pathways related to fibrosis and immune response, highlighting KYNA as a promising therapeutic candidate for kidney fibrosis.
Sýkorová et al. (Thu,) studied this question.