Abstract | BACKGROUND: METHODS: Western blot and immunohistochemical staining were used to examine protein expression, while qRT-PCR was used to examine mRNA expression. Coimmunoprecipitation, chromatin immunoprecipitation, RNA interference, and luciferase reporter gene analysis were employed to explore the mechanisms of PAA and melatonin's renoprotective effects. RESULTS: PAA and combined therapy exhibited renoprotective and antifibrotic effects, but the underlying mechanisms were different during AKI-to-CKD continuum. Melatonin suppressed Smad-dependent and Smad-independent pathways, while PAA selectively inhibited Smad3 phosphorylation through distrupting the interactions of Smad3 with TGFβRI and SARA. Further studies demonstrated that the inhibitory effects of melatonin and PAA were partially depended on Smad3, especially PAA. Melatonin and PAA also inhibited the Wnt/β- catenin pathway and its profibrotic downstream targets, and PAA performed better. We further determined that IRI induced a nuclear Smad3/β- catenin complex, while melatonin and PAA disturbed the interaction of Smad3 and β- catenin, and supplementing with PAA could enhance the inhibitory effects of melatonin on the TGF-β/Smad and Wnt/β- catenin pathways. CONCLUSIONS: Combined melatonin and PAA provides a promising therapeutic strategy to treat renal fibrosis during the AKI-to-CKD continuum.
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Authors | Dan-Qian Chen, Gang Cao, Hui Zhao, Lin Chen, Tian Yang, Ming Wang, Nosratola D Vaziri, Yan Guo, Ying-Yong Zhao |
Journal | Therapeutic advances in chronic disease
(Ther Adv Chronic Dis)
Vol. 10
Pg. 2040622319869116
( 2019)
ISSN: 2040-6223 [Print] United States |
PMID | 31452866
(Publication Type: Journal Article)
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