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
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
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Research Article Nephrology

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.

Authors

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

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Figure 7

GS-444217 halts the progressive decline of renal function in a mouse model of DKD.

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GS-444217 halts the progressive decline of renal function in a mouse mod...
(A–E) Ten-week-old db/db eNOS–/– mice were fed standard rodent chow (vehicle) or chow containing GS-444217 (0.3% by weight) for 8 weeks. A separate group of untreated db/db eNOS–/– mice were euthanized at 10 weeks of age to establish baseline-disease parameters. (A) GFR was measured using inulin-FITC clearance in baseline mice (week 10) and in treated mice (week 18). (B) Proteinuria (urinary albumin to creatinine ratio [UACR]) was measured at weeks 10, 14, and 18. (C) A sclerosis injury score was calculated at 18 weeks on periodic acid–Schiff–stained kidneys averaging the lesion scores of 80–100 glomeruli per mouse using the following scoring system: 0, no lesion; 1, sclerosis of up to 25% of the glomerulus; 2, sclerosis of 25%–50%; 3, sclerosis of 50%–75%; and 4, sclerosis of >75% of the glomerulus. (D and E) Image analysis and graphed pathology scores of renal sections stained for collagen deposition (collagen IV) (D) or podocyte loss (Wilms tumor antigen [WT-1]) (E). Scale bars: 100 μm (C), 50 μm (E), or 30 μm (D). Data in A–E are mean ± SEM, n = 9–12; *P < 0.05 vs. 10-week baseline by unpaired t test, †P < 0.05 vs. vehicle (ANOVA with Bonferroni’s multiple-comparisons test).