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
View: Text | PDF
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

×

Figure 5

GS-444217 inhibits acute renal tubular injury in rat kidney.

Options: View larger image (or click on image) Download as PowerPoint
GS-444217 inhibits acute renal tubular injury in rat kidney. (A–D) Renal...
(A–D) Renal ischemia/reperfusion (I/R) injury. GS-444217 (30 mg/kg) or vehicle (Veh; equal volume) was orally administered to Sprague-Dawley rats just before 30 minutes of bilateral renal ischemia. Parameters of renal function were assessed in serum and kidney following a 24-hour reperfusion period. (A and B) Serum creatinine and blood urea nitrogen concentrations. (C and D) Renal pathology scores for tubular necrosis (H&E-stained sections) and apoptosis/necrosis (TUNEL stain). Data in A–D are mean ± SEM, n = 5–8; *P < 0.05 vs. control, †P < 0.05 vs. I/R treated with vehicle (ANOVA with Bonferroni’s multiple-comparisons test). (E–N) Unilateral ureteral obstruction (UUO). Sprague-Dawley rats had sham or UUO surgery. GS-444217 (30 mg/kg) or vehicle (equal volume) was orally administered 1 hour before surgery and continued twice per day for 7 days. (E–G) Western blot analysis of kidney lysates for p-p38 and p-JNK. Dot plots show p-p38 and p-JNK levels normalized to tubulin loading control (NoTx, no treatment). (H–K, M, and N) Image analysis and graphed pathology scores of renal sections stained for collagen deposition (collagen IV) (scale bars: 50 μm) (H–K), cortical interstitial α-smooth muscle actin–positive (α-SMA–positive) myofibroblasts (M), and apoptosis/necrosis of kidney epithelial cells (TUNEL) (N). (L) Collagen I (Col1a1) mRNA was measured in whole kidney by reverse transcriptase PCR. Data in F, G, and K–N are mean ± SEM, n = 4 (sham), n = 8 (UUO); *P < 0.01 vs. sham surgery, †P < 0.01 vs. UUO treated with vehicle (ANOVA with Bonferroni’s multiple-comparisons test).