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.
Highlights
Peritoneal dialysis is one of the very few renal replacement therapeutic modalities available to patients with end-stage renal failure or uremia [1]
Peritoneal Fibrosis in the Mouse Model of Peritoneal Dialysis Is Improved by Salvianolic acid A (Sal A) Treatment, Concomitant With the Attenuation of GSK3β Hyperactivity
Peritoneal fibrosis was evident in the mouse model of peritoneal dialysis on week 7, as revealed by Masson trichrome staining for collagens (Figure 2A)
Summary
Peritoneal dialysis is one of the very few renal replacement therapeutic modalities available to patients with end-stage renal failure or uremia [1]. The peritoneal membrane is comprised mainly by the peritoneal mesothelial cells, which may dedifferentiate and acquire profibrogenic phenotypes upon long term exposure to a number of injurious factors, including sustained hypertonicity of peritoneal dialysis solutions, uremic toxins, peritonitis, infection and. In order to sustain a critical life-line for uremic patients, it is imperative to identify novel therapeutic targets and develop new treatments for preventing peritoneal fibrosis. Akin to fibrosis in other organ systems [3], peritoneal fibrosis is a complex yet well-orchestrated pathological process and involves oxidative stress, inflammation, maladaptive angiogenesis and other events [1]. Recent studies demonstrate that GSK3β is situated at the nexus of the Nrf and NFκB pathways and serves as a crucial regulator of the above pathological events [6, 7]. Burgeoning evidence has implicated GSK3β in the fibrogenesis of diverse tissues [8, 9], including peritoneal mesothelial cells [10]. Therapeutic targeting of GSK3β is likely a promising strategy to treat peritoneal fibrosis
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