ASK1 contributes to fibrosis and dysfunction in models of kidney disease
John T. Liles, … , Agnes B. Fogo, David G. Breckenridge
John T. Liles, … , Agnes B. Fogo, David G. Breckenridge
Published July 19, 2018
Citation Information: J Clin Invest. 2018;128(10):4485-4500. https://doi.org/10.1172/JCI99768.
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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 6

The ASK1 pathway is activated similarly in DKD patients and db/db eNOS–/– mice.

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The ASK1 pathway is activated similarly in DKD patients and db/db eNOS–/...
(A–J) Immunostaining for p-p38 was used as a measure of ASK1 pathway activation in kidney biopsies from donors without kidney disease (“normal,” n = 7) (A and C) and patients with DKD (n = 10) (B and D), and kidneys from 18-week-old db/db eNOS–/– mice treated with vehicle (standard rodent chow) (F and H) or with GS-444217 (0.3% in rodent chow) (G and I) for 8 weeks (n = 8–10). Representative images of glomerular (top panels) and tubulointerstitial compartments (bottom panels) are shown for human and mouse (scale bars: 100 μm). (E and J) Whole-slide images were analyzed with Definiens Developer XD and expressed as an H-Score that quantifies p-p38 staining intensity and distribution in kidney biopsies from DKD patients and controls (E) and in kidneys from 18-week-old db/db eNOS–/– mice treated with vehicle or with GS-444217 for 8 weeks (J) (mean ± SD; P value is shown on graph; unpaired t test).