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Title: | ASK1 contributes to fibrosis and dysfunction in models of kidney disease. | Authors: | Papalia G.A.;Fogo A.B.;Breckenridge D.G.;Yang H.;Koch K.A.;Wong M.H.;French D.M.;Altuhaifi T.;Liles J.T.;Corkey B.K.;Nikolic-Paterson D.J. ;Ma F.Y.;Notte G.T.;Budas G.R.;Lansdon E.B.;Hinojosa-Kirschenbaum F.;Badal S.S.;Lee M.;Huntzicker E.G.;Sullivan T.;Schultz B.E.;Wise S.;Pendem S.;Graupe M.;Castonguay L. | Institution: | (Castonguay) Ency2 Consulting, Denver, CO, United States (Koch) Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Denver, CO, United States (Ma, Nikolic-Paterson) Department of Nephrology, Monash University Centres for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, Australia (Altuhaifi) College of Medicine, Alfaisal University, Riyadh, Saudi Arabia (Yang, Fogo) Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States (Liles, Corkey, Notte, Budas, Lansdon, Hinojosa-Kirschenbaum, Badal, Lee, Schultz, Wise, Pendem, Graupe, Wong, Papalia, French, Sullivan, Huntzicker, Breckenridge) Department of Biology, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, United States | Issue Date: | 17-Oct-2018 | Copyright year: | 2018 | Publisher: | American Society for Clinical Investigation | Place of publication: | United States | Publication information: | Journal of Clinical Investigation. 128 (10) (pp 4485-4500), 2018. Date of Publication: 01 Oct 2018. | Journal: | Journal of Clinical Investigation | 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.Copyright © 2018 American Society for Clinical Investigation. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1172/JCI99768 | Link to associated publication: | Click here for full text options | PubMed URL: | 30024858 [http://www.ncbi.nlm.nih.gov/pubmed/?term=30024858] | ISSN: | 0021-9738 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/37193 | Type: | Article | Subjects: | nonhuman plasma half life priority journal protein phosphorylation proteinuria signal transduction systolic blood pressure alpha smooth muscle actin/ec [Endogenous Compound] *apoptosis signal regulating kinase 1/ec [Endogenous Compound] collagen type 1/ec [Endogenous Compound] *protein serine threonine kinase inhibitor/dt [Drug Therapy] *protein serine threonine kinase inhibitor/po [Oral Drug Administration] *protein serine threonine kinase inhibitor/pk [Pharmacokinetics] *protein serine threonine kinase inhibitor/pd [Pharmacology] stress activated protein kinase/ec [Endogenous Compound] *gs 444217/cb [Drug Combination] *gs 444217/dt [Drug Therapy] *gs 444217/po [Oral Drug Administration] *gs 444217/pk [Pharmacokinetics] *gs 444217/pd [Pharmacology] unclassified drug collagen type 4/ec [Endogenous Compound] enalapril/cb [Drug Combination] messenger RNA/ec [Endogenous Compound] mitogen activated protein kinase p38/ec [Endogenous Compound] *protein serine threonine kinase inhibitor/cb [Drug Combination] *acute kidney failure animal experiment animal model animal tissue article autophosphorylation B lymphocyte chronic kidney failure/dt [Drug Therapy] controlled study crystallography diabetic nephropathy drug bioavailability drug design drug structure enzyme activation enzyme active site *enzyme inhibition enzyme kinetics enzyme phosphorylation fluorescence resonance energy transfer glomerular dysfunction glomerulosclerosis glomerulus filtration rate HEK293T cell line hypertension immunohistochemistry inflammation kidney biopsy *kidney fibrosis/dt [Drug Therapy] *kidney injury/dt [Drug Therapy] monotherapy mouse drug design drug structure enzyme activation enzyme active site *enzyme inhibition enzyme kinetics controlled study fluorescence resonance energy transfer glomerular dysfunction glomerulosclerosis glomerulus filtration rate HEK293T cell line hypertension immunohistochemistry inflammation kidney biopsy *kidney fibrosis / *drug therapy *kidney injury / *drug therapy monotherapy mouse nonhuman plasma half life priority journal protein phosphorylation proteinuria signal transduction systolic blood pressure chronic kidney failure / drug therapy B lymphocyte autophosphorylation Article animal tissue animal model animal experiment *acute kidney failure enzyme phosphorylation crystallography diabetic nephropathy drug bioavailability |
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