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Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome.
Savira, Feby; Cao, Longxing; Wang, Ian; Yang, Wendi; Huang, Kevin; Hua, Yue; Jucker, Beat M; Willette, Robert N; Huang, Li; Krum, Henry; Li, Zhiliang; Fu, Qiang; Wang, Bing Hui.
Afiliación
  • Savira F; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Cao L; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Wang I; Zhujiang Hospital, School of Medicine, Southern Medical University, Guangzhou, China.
  • Yang W; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Huang K; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Hua Y; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Jucker BM; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Willette RN; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
  • Huang L; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
  • Krum H; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
  • Li Z; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Fu Q; Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
  • Wang BH; Zhujiang Hospital, School of Medicine, Southern Medical University, Guangzhou, China.
PLoS One ; 12(11): e0187459, 2017.
Article en En | MEDLINE | ID: mdl-29107962
Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and ß-MHC) and pro-fibrotic genes (TGF-ß1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Toxinas Biológicas / Cardiomegalia / MAP Quinasa Quinasa Quinasa 5 / Síndrome Cardiorrenal Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Toxinas Biológicas / Cardiomegalia / MAP Quinasa Quinasa Quinasa 5 / Síndrome Cardiorrenal Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2017 Tipo del documento: Article País de afiliación: Australia