Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 35, Issue 1, Pages 74-85Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfz073
Keywords
compound K; mechanically induced constant pressure; mitochondria; NLRP3 inflammasome; renal tubulointerstitial lesions
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Funding
- Ministry of Science and Technology [MOST 106-2320-B-016-012-MY3]
- Ministry of National Defense-Medical Affairs Bureau from National Defense Medical Center [MAB-106-007, MAB107-042]
- Tri-Service General Hospital, Taipei, Taiwan [TSGH-C107-063]
- Molecular Medicine Research Center, Chang Gung University from The Featured Areas Research Center Program within the framework of the Higher ducation Sprout Project by the Ministry of Education, Taiwan
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Background. Renal tubulointerstitial lesions (TILs), a key pathological hallmark for chronic kidney disease to progress to end-stage renal disease, feature renal tubular atrophy, interstitial mononuclear leukocyte infiltration and fibrosis in the kidney. Our study tested the renoprotective and therapeutic effects of compound K (CK), as described in our US patent (US7932057B2), on renal TILs using a mouse unilateral ureteral obstruction (UUO) model. Methods. Renal pathology was performed and renal draining lymph nodes were subjected to flow cytometry analysis. Mechanism-based experiments included the analysis of mitochondrial dysfunction, a model of tubular epithelial cells (TECs) under mechanically induced constant pressure (MICP) and tandemmass tags (TMT)-based proteomics analysis. Results. Administration of CK ameliorated renal TILs by reducing urine levels of proinflammatory cytokines, and preventing mononuclear leukocyte infiltration and fibrosis in the kidney. The beneficial effects clearly correlated with its inhibition of: (i) NF-kappa B-associated priming and the mitochondria-associated activating signals of the NLRP3 inflammasome; (ii) STAT3 signalling, which in part prevents NLRP3 inflammasome activation; and (iii) the TGF-beta-dependent Smad2/Smad3 fibrotic pathway, in renal tissues, renal TECs under MICP and/or activated macrophages, the latter as a major inflammatory player contributing to renal TILs. Meanwhile, TMT-based proteomics analysis revealed downregulated renal NLRP3 inflammasome activation-associated signalling pathways in CK-treated UUOmice.0 Conclusions. The present study, for the first time, presents the potent renoprotective and therapeutic effects of CK on renal TILs by targeting the NLRP3 inflammasome and STAT3 signalling.
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