Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation

Abstract

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.

Fluorofenidone attenuates interleukin‐1β production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction

“…Previous studies showed that renal inflammation played an important role in the development of renal fibrosis . AKF‐PD, a novel low‐molecular‐weight pyridine agent, exerts strong anti‐fibrotic effect . In this study, we found that treatment with AKF‐PD reduced the deposition of collagens and attenuated kidney interstitial fibrosis in UUO.…”

“…2 AKF-PD, a novel low-molecular-weight pyridine agent, exerts strong anti-fibrotic effect. [27][28][29][30] In this study, we found that treatment with AKF-PD reduced the deposition of collagens and attenuated kidney interstitial fibrosis in UUO. Furthermore, AKF-PD treatment significantly ameliorated UUO-induced leukocytes infiltration.…”

Periplaneta Americana Extract May Attenuate Renal Fibrosis through Inhibiting Janus Tyrosine Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway

“…Just as previously described, the JAK2/STAT3 pathway may contribute to the progression of renal interstitial fibrosis [12, 18]. Many drugs attenuate renal fibrosis by targeting the JAK2/STAT3 pathway.…”

“…Many drugs attenuate renal fibrosis by targeting the JAK2/STAT3 pathway. It has been indicated that fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation [12]. And Zhang et al[8] found that Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling.…”

“…Inhibiting STAT3 activation could slow the progress of renal fibrosis and knockdown of STAT3-protected STZ diabetic mice against extracellular matrix deposition [9-11]. It has been reported that JAK/STAT, especially JAK2/STAT3, is involved in renal fibrosis [12]. Interestingly, Song et al [1] have reported that the PAEs could promote the healing of skin wounds by targeting the JAK/STAT3 pathway.…”