Therapeutic Targeting of GSK3β-Regulated Nrf2 and NFκB Signaling Pathways by Salvianolic Acid A Ameliorates Peritoneal Fibrosis

Abstract

Peritoneal fibrosis is a devastating complication in patients undergoing peritoneal dialysis, with no definite therapy yet available. Salvia miltiorrhiza and its major active component Salvianolic acid A (Sal A) have demonstrated a beneficial effect in myriad diseases. However, their effect on peritoneal fibrosis is unknown. In murine models of peritoneal dialysis, daily Sal A treatment substantially improved the peritoneal dialysis fluid (PDF) elicited peritoneal fibrosis, marked by thickening of the submesothelial compact zone, accumulation of extracellular matrix and increased expression of vimentin and PAI-1, concomitant with attenuation of GSK3β hyperactivity. This coincided with diminished nitrotyrosine in peritoneal tissues and increased Nrf2 nuclear translocation, entailing a lessened oxidative injury and reinforced Nrf2 antioxidant response. Meanwhile, inflammatory infiltration and maladaptive angiogenesis in peritoneal tissues provoked by PDF injury were also mitigated by Sal A, associated with a suppressed NFκB activation. Mechanistically, ectopic expression of the constitutively active GSK3β blunted the NFκB-suppressing and Nrf2-activating efficacy of Sal A in peritoneal mesothelial cells exposed to hypertonic dextrose, suggesting that GSK3β inhibition mediates the protective effect of Sal A. Collectively, our findings may open the avenue for developing a novel therapy based on Sal A for preventing peritoneal fibrosis in peritoneal dialysis.

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis

“…Glycogen synthase kinase 3 beta (GSK3β) has been associated with inflammation and fibrogenesis in different tissues [ 175 , 176 ]. In PDF-exposed mice, a peritoneal hyperactivity of GSK3β (characterized by increased GSK3β expression and reduced inhibitory phosphorylation at serine 9) has been found [ 177 ]. Accordingly, the therapeutic targeting of GSK3β by Salvianolic Acid A improved peritoneal fibrosis together with attenuated expression of the inflammatory cytokines IL-1 β, TNF-α, and MCP-1, prevented activation of NF-κB signaling pathway, reinforced the nuclear factor-erythroid 2-related factor 2 (NRF2) antioxidant response, and diminished oxidative injury [ 177 ].…”

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress

“…The NF-κB signaling pathway is a key mechanism involved in the inflam immune responses. In several peritoneal damage models, the activation o pathway has been reported [26,27]. In mice treated with CHX for 10 days, w creased levels of the phosphorylated NF-κB subunit p65 (p-NF-κB p65) and lated levels of the NF-κB inhibitor IκBα (p-IκBα), which indicate the activatio…”