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ASK1 contributes to fibrosis and dysfunction in models of kidney disease.

Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, Badal SS, Lee M, Schultz BE, Wise S, Pendem S, Graupe M, Castonguay L, Koch KA, Wong MH, Papalia GA, French DM, Sullivan T, Huntzicker EG, Ma FY, Nikolic-Paterson DJ, Altuhaifi T, Yang H, Fogo AB, Breckenridge DG
J Clin Invest 128 4485-4500 (2018)
Related entries: 6e2n, 6e2o

Cited: 57 times
EuropePMC logo PMID: 30024858

Abstract

Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.

Reviews citing this publication (23)

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Articles citing this publication (34)

  1. Effects of Selonsertib in Patients with Diabetic Kidney Disease. Chertow GM, Pergola PE, Chen F, Kirby BJ, Sundy JS, Patel UD, GS-US-223-1015 Investigators. J Am Soc Nephrol 30 1980-1990 (2019)
  2. Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension. Meijles DN, Cull JJ, Markou T, Cooper STE, Haines ZHR, Fuller SJ, O'Gara P, Sheppard MN, Harding SE, Sugden PH, Clerk A. Hypertension 76 1208-1218 (2020)
  3. Shenyan Kangfu tablet alleviates diabetic kidney disease through attenuating inflammation and modulating the gut microbiota. Chen Q, Ren D, Wu J, Yu H, Chen X, Wang J, Zhang Y, Liu M, Wang T. J Nat Med 75 84-98 (2021)
  4. Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells. Yoon YC, Fang Z, Lee JE, Park JH, Ryu JK, Jung KH, Hong SS. Biomol Ther (Seoul) 28 527-536 (2020)
  5. Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin. Zheng XP, Nie Q, Feng J, Fan XY, Jin YL, Chen G, Du JW. BMC Nephrol 21 174 (2020)
  6. Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury. Sang Y, Tsuji K, Inoue-Torii A, Fukushima K, Kitamura S, Wada J. Int J Mol Sci 21 E4099 (2020)
  7. Azilsartan Modulates HMGB1/NF-κB/p38/ERK1/2/JNK and Apoptosis Pathways during Renal Ischemia Reperfusion Injury. Alaaeldin R, Bakkar SM, Mohyeldin RH, Ali FEM, Abdel-Maqsoud NMR, Fathy M. Cells 12 185 (2023)
  8. Apoptosis signal-regulating kinase 1 (ASK1) inhibition reduces endothelial cytokine production without improving permeability after toll-like receptor 4 (TLR4) challenge. Miller MR, Koch SR, Choi H, Lamb FS, Stark RJ. Transl Res 235 115-128 (2021)
  9. Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy. Papanicolaou KN, Jung J, Ashok D, Zhang W, Modaressanavi A, Avila E, Foster DB, Zachara NE, O'Rourke B. J Biol Chem 299 102907 (2023)
  10. Recombinant Long-Acting Thioredoxin Ameliorates AKI to CKD Transition via Modulating Renal Oxidative Stress and Inflammation. Nishida K, Watanabe H, Murata R, Tokumaru K, Fujimura R, Oshiro S, Nagasaki T, Miyahisa M, Hiramoto Y, Nosaki H, Imafuku T, Maeda H, Fukagawa M, Maruyama T. Int J Mol Sci 22 5600 (2021)
  11. ASK1 Enhances Angiotensin II-Induced Liver Fibrosis In Vitro by Mediating Endoplasmic Reticulum Stress-Dependent Exosomes. Fang PP, Pan CW, Lin W, Li J, Huang SS, Zhou GY, Du WJ, Li Q. Mediators Inflamm 2020 8183713 (2020)
  12. Exploring molecular targets in diabetic kidney disease. Maruno S, Tanaka T, Nangaku M. Kidney Res Clin Pract 41 S33-S45 (2022)
  13. Mechanisms of Trx2/ASK1-Mediated Mitochondrial Injury in Pemphigus Vulgaris. Wei B, Li F. Biomed Res Int 2021 2471518 (2021)
  14. Letter ASK1 inhibition triggers platelet apoptosis via p38-MAPK-mediated mitochondrial dysfunction. Manikanta K, Naveen Kumar SK, Hemshekhar M, Kemparaju K, Girish KS. Haematologica 105 e419-e423 (2020)
  15. Demystifying Chronic Kidney Disease of Unknown Etiology (CKDu): Computational Interaction Analysis of Pesticides and Metabolites with Vital Renal Enzymes. Rajapaksha H, Pandithavidana DR, Dahanayake JN. Biomolecules 11 261 (2021)
  16. Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy. Chen A, Xu J, Lai H, D'Agati VD, Guan TJ, Badal S, Liles J, He JC, Lee K. Nephrol Dial Transplant 36 430-441 (2021)
  17. The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction. Ding J, Cui S, Li SY, Cui LY, Nan QY, Lin XJ, Xuan MY, Jin J, Piao SG, Jiang YJ, Zheng HL, Jin JZ, Chung BH, Yang CW, Cui JH, Li C. PLoS One 18 e0286903 (2023)
  18. ASK1-ER stress pathway-mediated fibrotic-EV release contributes to the interaction of alveolar epithelial cells and lung fibroblasts to promote mechanical ventilation-induced pulmonary fibrosis. Tang R, Mei S, Xu Q, Feng J, Zhou Y, Xing S, He Z, Gao Y. Exp Mol Med 54 2162-2174 (2022)
  19. c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease. Smith AO, Jonassen JA, Preval KM, Davis RJ, Pazour GJ. J Cell Signal 3 62-78 (2022)
  20. Comment ASK1 Inhibitor in Chronic Kidney Disease Therapy: From Bench to Bedside. Wen L, Wei Q. Kidney360 3 1128-1131 (2022)
  21. ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death. Ogier JM, Gao Y, Dunne EM, Wilson MA, Ranganathan SC, Tesch GH, Nikolic Paterson DJ, Dabdoub A, Burt RA, Nayagam BA, Lockhart PJ. J Mol Med (Berl) 100 797-813 (2022)
  22. Comprehensive analysis of the relationship between xanthine oxidoreductase activity and chronic kidney disease. Zhang Y, Ding X, Guo L, Zhong Y, Xie J, Xu Y, Li H, Zheng D. iScience 26 107332 (2023)
  23. Single Nucleotide Polymorphisms of IL-33 Gene Correlated with Renal Allograft Fibrosis in Kidney Transplant Recipients. Liu X, Liu K, Gui Z, Feng D, Wang Z, Zheng M, Fei S, Chen H, Sun L, Han Z, Ju X, Zhang H, Tan R, Gu M. J Immunol Res 2021 8029180 (2021)
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  28. Investigating the Mechanism of Inhibition of Cyclin-Dependent Kinase 6 Inhibitory Potential by Selonsertib: Newer Insights Into Drug Repurposing. Baig MH, Yousuf M, Khan MI, Khan I, Ahmad I, Alshahrani MY, Hassan MI, Dong JJ. Front Oncol 12 865454 (2022)
  29. Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model. Badal SS, Al Tuhaifi T, Yu YF, Lopez D, Plato CT, Joly K, Breckenridge DG, Yang HC, Liles JT, Fogo AB. Kidney360 3 1169-1182 (2022)
  30. ASK1/ p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer. Peng Z, Wei G, Huang P, Matta H, Gao W, An P, Zhao S, Lin Y, Tan L, Vaid K, Skelton-Badlani D, Nasser I, Budas G, Lopez D, Li L, Breckenridge D, Myers R, McHutchison J, Kuang M, Popov YV, Popov YV. Hepatology 80 346-362 (2024)
  31. Comment ASK1ng to Delay the Progression of Pulmonary Fibrosis. Schuliga M, Madala SK. Am J Respir Cell Mol Biol 66 465-467 (2022)
  32. Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal-regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment. Zaky YA, Rashad MW, Zaater MA, El Kerdawy AM. BMC Chem 18 2 (2024)
  33. Kaempferol sophoroside glucoside mitigates acetaminophen-induced hepatotoxicity: Role of Nrf2/NF-κB and JNK/ASK-1 signaling pathways. Mohamed GA, El-Agamy DS, Abdallah HM, Sindi IA, Almogaddam MA, Alzain AA, Andijani YS, Ibrahim SRM. Heliyon 10 e31448 (2024)
  34. Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors. Han X, Lan P, Chen Q, Liu H, Chen Z, Wang T, Wang Z. J Enzyme Inhib Med Chem 39 2414382 (2024)


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