ASK1 contributes to fibrosis and dysfunction in models of kidney disease
| العنوان: | ASK1 contributes to fibrosis and dysfunction in models of kidney disease |
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| المؤلفون: | David G. Breckenridge, Laurie A. Castonguay, Giuseppe A. Papalia, Swetha Pendem, Shawn S. Badal, Ford Hinojosa-Kirschenbaum, Gregory T. Notte, Sarah Wise, Michael V. Lee, Keith A. Koch, Agnes B. Fogo, Dorothy French, Britton Kenneth Corkey, Frank Y. Ma, Brian E. Schultz, Eric B. Lansdon, Melanie H. Wong, David J. Nikolic-Paterson, Tareq M Al-Tuhaifi, Theodore Sullivan, Michael Graupe, Haichun Yang, Erik Huntzicker, Grant R. Budas, John T. Liles |
| المصدر: | Journal of Clinical Investigation. 128:4485-4500 |
| بيانات النشر: | American Society for Clinical Investigation, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Nephrology, medicine.medical_specialty, MAP Kinase Signaling System, Kidney Glomerulus, Renal function, MAP Kinase Kinase Kinase 5, Rats, Sprague-Dawley, Mice, Random Allocation, 03 medical and health sciences, Fibrosis, Internal medicine, medicine, Animals, Humans, Diabetic Nephropathies, ASK1, Protein Kinase Inhibitors, Mice, Knockout, Serine/threonine-specific protein kinase, Kidney, business.industry, Glomerulosclerosis, General Medicine, Fibroblasts, medicine.disease, Oxidative Stress, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cancer research, Female, business, Research Article, Kidney disease |
| الوصف: | 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. |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::38b037ace289b522c4f72e5fa892d048 https://doi.org/10.1172/jci99768 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....38b037ace289b522c4f72e5fa892d048 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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