PMID- 29107962 OWN - NLM STAT- MEDLINE DCOM- 20171128 LR - 20181113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 11 DP - 2017 TI - Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome. PG - e0187459 LID - 10.1371/journal.pone.0187459 [doi] LID - e0187459 AB - 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 (alpha-skeletal muscle actin and beta-MHC) and pro-fibrotic genes (TGF-beta1 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-kappaB) 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. FAU - Savira, Feby AU - Savira F AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Cao, Longxing AU - Cao L AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. AD - Zhujiang Hospital, School of Medicine, Southern Medical University, Guangzhou, China. FAU - Wang, Ian AU - Wang I AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Yang, Wendi AU - Yang W AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Huang, Kevin AU - Huang K AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Hua, Yue AU - Hua Y AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China. FAU - Jucker, Beat M AU - Jucker BM AD - Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America. FAU - Willette, Robert N AU - Willette RN AD - Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America. FAU - Huang, Li AU - Huang L AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Krum, Henry AU - Krum H AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. FAU - Li, Zhiliang AU - Li Z AD - Zhujiang Hospital, School of Medicine, Southern Medical University, Guangzhou, China. FAU - Fu, Qiang AU - Fu Q AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. AD - Zhujiang Hospital, School of Medicine, Southern Medical University, Guangzhou, China. FAU - Wang, Bing Hui AU - Wang BH AUID- ORCID: 0000-0001-9580-2548 AD - Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. LA - eng PT - Journal Article DEP - 20171106 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Cresols) RN - 0 (NF-kappa B) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Sulfuric Acid Esters) RN - 0 (Toxins, Biological) RN - 0 (uremia middle molecule toxins) RN - 56M34ZQY1S (4-cresol sulfate) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5) RN - N187WK1Y1J (Indican) SB - IM MH - Animals MH - Cardio-Renal Syndrome/*pathology MH - Cardiomegaly/*prevention & control MH - Cells, Cultured MH - Cresols/pharmacology MH - Fibrosis MH - Indican/pharmacology MH - MAP Kinase Kinase Kinase 5/*antagonists & inhibitors MH - Mitogen-Activated Protein Kinases/metabolism MH - NF-kappa B/metabolism MH - Protein Kinase Inhibitors/pharmacology MH - Rats MH - Sulfuric Acid Esters/pharmacology MH - Toxins, Biological/*toxicity PMC - PMC5673193 COIS- Competing Interests: B.M.J and R.N.W are employees of GlaxoSmithKline and are involved in the development of G226. This does not alter our adherence to PLOS ONE policies on sharing data and materials. EDAT- 2017/11/07 06:00 MHDA- 2017/11/29 06:00 PMCR- 2017/11/06 CRDT- 2017/11/07 06:00 PHST- 2017/04/12 00:00 [received] PHST- 2017/10/22 00:00 [accepted] PHST- 2017/11/07 06:00 [entrez] PHST- 2017/11/07 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2017/11/06 00:00 [pmc-release] AID - PONE-D-17-14221 [pii] AID - 10.1371/journal.pone.0187459 [doi] PST - epublish SO - PLoS One. 2017 Nov 6;12(11):e0187459. doi: 10.1371/journal.pone.0187459. eCollection 2017.