Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Abstract

Aim: To explore the relationship between the signal transducer and activator of transcription 3 (STAT3) signaling and renal fibrosis. Methods: Rat renal tubular epithelial NRK-52E cells were treated with angiotensin II (Ang II), nicotinamide (an inhibitor of NAD + -dependent class III protein deacetylases, SIRT1-7), or resveratrol (an activator of SIRT1). Mice underwent unilateral ureteral obstruction (UUO) were used for in vivo studies. Renal interstitial fibrosis was observed with HE and Masson's trichrome staining. STAT3 acetylation and phosphorylation, fibronectin, collagen I, collagen IV, and α-smooth muscle actin (α-SMA) levels were examined using Western blotting. Results: Nicotinamide (0.625-10 mmol/L) dose-dependently increased STAT3 acetylation on Lys685 and phosphorylation on Tyr705 in NRK-52E cells, accompanied by accumulation of fibronectin and collagen IV. Ang II increased STAT3 phosphorylation on Tyr705 and the expression of fibronectin, collagen IV and α-SMA in the cells. Pretreatment with resveratrol (12.5 μmol/L) blocked Ang II-induced effects in the cells. UUO induced marked STAT3 phosphorylation, fibronectin, collagen IV and α-SMA accumulation, and renal interstitial fibrosis in the obstructed kidneys, which were significantly attenuated by daily administration of resveratrol (100 mg/kg). Conclusion: STAT3 acetylation plays an important role in activation of STAT3 signaling pathway and consequent renal fibrosis.

Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation‐related signalling pathways

“…Previous studies have shown that the proliferation‐related signalling pathways, including PI3K/Akt, Wnt/β‐catenin, JAK2/STAT3, and MAPK, are involved in myofibroblast transformation and fibrosis in various diseases (Gao et al, ; Liu et al, ; Tan, Zhou, Zhou, & Liu, ). For instance, the JAK2/STAT3 pathway, an important signal transduction cascade with a wide range of expressed cytokines and growth factors, is involved in cell cycle progression and proliferative cell transformation (Ni et al, ). The MAPK pathway has been shown to contribute to the TGF‐β1‐induced phenotypic transformation of human lung fibroblasts into myofibroblasts (Caraci et al, ).…”

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

“…HDAC1 and HDAC2 can promote the deacetylation of STAT1, which prevents its binding to and inhibition of NF-κB allowing the latter to stimulate a pro-fibrogenic transcription program in mesangial cells (Kumar et al, 2017). The acetylation status and thus activity of STAT3, a pro-fibrogenic transcription factor, can also be modulated by HDACs during renal fibrosis (Ni et al, 2014). Since specific non-histone substrates for HDAC11 have yet to be identified, profiling the HDAC11 interactome in the kidneys may provide novel insight into its mode of action in the context of renal fibrosis.…”

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

“…Increasing evidence has suggested that the STAT3 pathway is highly related to renal fibrosis. 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].…”