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ASK1 contributes to fibrosis and dysfunction in models of kidney disease

John T Liles1, Britton K Corkey1, Gregory T Notte1

  • 1Gilead Sciences, Foster City, California, USA.

The Journal of Clinical Investigation
|July 20, 2018
PubMed

Insights

A new drug, GS-444217, inhibits Apoptosis Signal-Regulating Kinase 1 (ASK1), reducing kidney injury and fibrosis. This ASK1 inhibitor shows promise for treating diabetic kidney disease (DKD) and slowing disease progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Oxidative stress is a key factor in acute and chronic kidney diseases.
  • Apoptosis signal-regulating kinase 1 (ASK1) is a redox-sensitive kinase that mediates apoptotic, inflammatory, and fibrotic signaling.
  • ASK1 pathway activation is observed in kidney biopsies from patients with diabetic kidney disease (DKD).

Purpose of the Study:

  • To discover and characterize a novel small-molecule inhibitor of ASK1, GS-444217.
  • To evaluate the therapeutic potential of ASK1 inhibition in reducing kidney injury and fibrosis.
  • To investigate the efficacy of GS-444217 in rodent models of DKD and in combination with enalapril.

Main Methods:

  • Discovery and characterization of GS-444217, a selective ASK1 inhibitor.
  • Confirmation of ASK1 pathway activation in renal biopsies from DKD patients.
  • Administration of GS-444217 in rodent models of kidney injury and fibrosis.
  • Assessment of combination therapy with enalapril.

Main Results:

  • GS-444217 effectively decreased ASK1 pathway activation in rodent models of kidney disease.
  • Treatment with GS-444217 reduced kidney inflammation and fibrosis, halting the decline in glomerular filtration rate.
  • Combination therapy of GS-444217 and enalapril enhanced proteinuria reduction and glomerulosclerosis regression.

Conclusions:

  • ASK1 is identified as a significant therapeutic target for renal diseases.
  • GS-444217 demonstrates significant potential for treating DKD by mitigating injury and fibrosis.
  • Further clinical development of ASK1 inhibitors is warranted for DKD treatment.
Keywords:
ApoptosisChronic kidney diseaseFibrosisNephrologyTherapeutics

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