Wan-Han Hsu1, Kuo-Feng Hua2, Li-Heng Tuan3, Yu-Ling Tsai3, Lichieh Julie Chu4, Yu-Chieh Lee2, Wei-Ting Wong1, Sheau-Long Lee5, Jenn-Haung Lai6, Ching-Liang Chu7, Ling-Jun Ho8, Hsiao-Wen Chiu1, Yu-Juei Hsu9, Cheng-Hsu Chen10,11,12, Shuk-Man Ka1,13, Ann Chen1,3. 1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. 2. Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. 3. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. 4. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 5. Department of Chemistry, R.O.C. Military Academy, Kaohsiung, Taiwan. 6. Department of Internal Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 7. Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan. 8. Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan. 9. Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. 10. Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 11. Department of Life Science, Tunghai University, Taichung, Taiwan. 12. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan. 13. Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
Abstract
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 tandem mass 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-κB-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-β-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 UUO mice. 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.
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 mouseunilateral 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 tandem mass 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-κB-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-β-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 UUO mice. 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.
Authors: Ana Karina Aranda-Rivera; Anjali Srivastava; Alfredo Cruz-Gregorio; José Pedraza-Chaverri; Shrikant R Mulay; Alexandra Scholze Journal: Antioxidants (Basel) Date: 2022-01-27