ASK1 contributes to fibrosis and dysfunction in models of kidney disease

John T. Liles; Britton K. Corkey; Gregory T. Notte; Grant R. Budas; Eric B. Lansdon; Ford Hinojosa-Kirschenbaum; Shawn S. Badal; Michael Lee; Brian E. Schultz; Sarah Wise; Swetha Pendem; Michael Graupe; Laurie Castonguay; Keith A. Koch; Melanie H. Wong; Giuseppe A. Papalia; Dorothy M. French; Theodore Sullivan; Erik G. Huntzicker; Frank Y. Ma; David J. Nikolic-Paterson; Tareq Altuhaifi; Haichun Yang; Agnes B. Fogo; David G. Breckenridge

doi:10.1172/JCI99768

ASK1 contributes to fibrosis and dysfunction in models of kidney disease

John T. Liles, Britton K. Corkey, Gregory T. Notte, Grant R. Budas, Eric B. Lansdon, Ford Hinojosa-Kirschenbaum, Shawn S. Badal, Michael Lee, Brian E. Schultz, Sarah Wise, Swetha Pendem, Michael Graupe, Laurie Castonguay, Keith A. Koch, Melanie H. Wong, Giuseppe A. Papalia, Dorothy M. French, Theodore Sullivan, Erik G. Huntzicker, Frank Y. MaDavid J. Nikolic-Paterson, Tareq Altuhaifi, Haichun Yang, Agnes B. Fogo, David G. Breckenridge

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4485-4500
Number of pages	16
Journal	Journal of Clinical Investigation
Volume	128
Issue number	10
DOIs	https://doi.org/10.1172/JCI99768
State	Published - Oct 1 2018

ASJC Scopus subject areas

General Medicine

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Liles, J. T., Corkey, B. K., Notte, G. T., Budas, G. R., Lansdon, E. B., Hinojosa-Kirschenbaum, F., Badal, S. S., Lee, M., Schultz, B. E., Wise, S., Pendem, S., Graupe, M., Castonguay, L., Koch, K. A., Wong, M. H., Papalia, G. A., French, D. M., Sullivan, T., Huntzicker, E. G., ... Breckenridge, D. G. (2018). ASK1 contributes to fibrosis and dysfunction in models of kidney disease. Journal of Clinical Investigation, 128(10), 4485-4500. https://doi.org/10.1172/JCI99768

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 2018, 'ASK1 contributes to fibrosis and dysfunction in models of kidney disease', Journal of Clinical Investigation, vol. 128, no. 10, pp. 4485-4500. https://doi.org/10.1172/JCI99768

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title = "ASK1 contributes to fibrosis and dysfunction in models of kidney disease",

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.",

author = "Liles, {John T.} and Corkey, {Britton K.} and Notte, {Gregory T.} and Budas, {Grant R.} and Lansdon, {Eric B.} and Ford Hinojosa-Kirschenbaum and Badal, {Shawn S.} and Michael Lee and Schultz, {Brian E.} and Sarah Wise and Swetha Pendem and Michael Graupe and Laurie Castonguay and Koch, {Keith A.} and Wong, {Melanie H.} and Papalia, {Giuseppe A.} and French, {Dorothy M.} and Theodore Sullivan and Huntzicker, {Erik G.} and Ma, {Frank Y.} and Nikolic-Paterson, {David J.} and Tareq Altuhaifi and Haichun Yang and Fogo, {Agnes B.} and Breckenridge, {David G.}",

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T1 - ASK1 contributes to fibrosis and dysfunction in models of kidney disease

AU - Liles, John T.

AU - Corkey, Britton K.

AU - Notte, Gregory T.

AU - Budas, Grant R.

AU - Lansdon, Eric B.

AU - Hinojosa-Kirschenbaum, Ford

AU - Badal, Shawn S.

AU - Lee, Michael

AU - Schultz, Brian E.

AU - Wise, Sarah

AU - Pendem, Swetha

AU - Graupe, Michael

AU - Castonguay, Laurie

AU - Koch, Keith A.

AU - Wong, Melanie H.

AU - Papalia, Giuseppe A.

AU - French, Dorothy M.

AU - Sullivan, Theodore

AU - Huntzicker, Erik G.

AU - Ma, Frank Y.

AU - Nikolic-Paterson, David J.

AU - Altuhaifi, Tareq

AU - Yang, Haichun

AU - Fogo, Agnes B.

AU - Breckenridge, David G.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

ER -

ASK1 contributes to fibrosis and dysfunction in models of kidney disease

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