Abstract
Accumulating evidence suggests that the pineal hormone melatonin displays protective effects against renal fibrosis, but the mechanisms remain poorly understood. Here, we investigate the effect of the pineal hormone on transdifferentiation of renal fibroblasts to myofibroblasts invoked by transforming growth factor-β1 (TGF-β1). Increased proliferation and activation of renal interstitial fibroblasts after TGF-β1 treatment were attenuated by melatonin pretreatment. Mechanistically, melatonin suppressed Smad2/3 phosphorylation and nuclear co-localization of their phosphorylated forms and Smad4 after TGF-β1 stimulation. In addition, increased phosphorylations of Akt, extracellular signal-regulated kinase 1/2, and p38 after TGF-β1 treatment were also suppressed by the hormone. These effects of melatonin were not affected by pharmacological and genetic inhibition of its membrane receptors. Furthermore, melatonin significantly reversed an increase of intracellular reactive oxygen species (ROS) and malondialdehyde levels, and a decrease of the reduced glutathione/oxidized glutathione ratio after TGF-β1 treatment. Finally, TGF-β1-induced proliferation and activation were also suppressed by N-acetylcysteine. Altogether, these findings suggest that the pineal hormone melatonin prevents TGF-β1-induced transdifferentiation of renal interstitial fibroblasts to myofibroblasts via inhibition of Smad and non-Smad signaling cadcades by inhibiting ROS-mediated mechanisms in its receptor-independent manner.
Highlights
Renal fibrosis is critically involved in the pathogenesis of chronic kidney disease (CKD) and attributed to excessive deposition of extracellular matrix (ECM)
To more clearly demonstrate that the inhibitory effects of melatonin on fibroblast-myofibroblast transdifferentiation is independent of its receptors, we examined the effects of genetic inhibition of melatonin receptor type 1A (MT1) and MT2 using small interfering RNA (siRNA) on the action of the hormone
We found that knockdown of melatonin receptors (MT1 and MT2) using siRNA did not significantly affect the inhibitory effects of the hormone on Transforming growth factor-β1 (TGF-β1)-induced proliferation (Figure 5A) and expression of fibronectin and α-SMA (Figure 5B–D)
Summary
Renal fibrosis is critically involved in the pathogenesis of chronic kidney disease (CKD) and attributed to excessive deposition of extracellular matrix (ECM). Fibroblast-myofibroblast transdifferentiation is one of the critical steps in the fibrotic process. Blocking fibroblast-myofibroblast transdifferentiation would be a promising preventive or therapeutic approach against renal fibrosis. Transforming growth factor-β1 (TGF-β1) is a crucial mediator in the pathophysiology of fibrotic diseases such as renal fibrosis [2,3]. Its downstream signaling involves Smad and non-Smad signaling cascades that regulate gene expression required for fibrotic processes including fibroblast-myofibroblast transdifferentiation. TGF-β1 induces phosphorylation of Smad proteins including Smad and Smad, which form complexes with Smad4 [2]. The cytokine can activate various non-Smad signaling pathways such as Akt and mitogen-activated protein kinase (MAPK)
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