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Targeting apoptosis signal-regulating kinase 1 in acute and chronic kidney disease

Greg H Tesch1,2, Frank Y Ma1,2, David J Nikolic-Paterson1,2

  • 1Department of Nephrology, Monash University, Victoria, Australia.

Anatomical Record (Hoboken, N.J. : 2007)
|January 24, 2020
PubMed

Insights

Targeting apoptosis signal-regulating kinase 1 (ASK1) effectively treats kidney diseases by inhibiting harmful p38 MAPK and JNK pathways. ASK1 inhibitors show promise in preclinical models and are now being tested in patients with diabetic kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase upstream of p38 MAPK and JNK.
  • p38 MAPK and JNK activation contribute to kidney disease pathogenesis.
  • ASK1 is activated in pathological states and not essential for homeostasis, making it a potential therapeutic target.

Purpose of the Study:

  • To review preclinical studies on ASK1 blockade in acute and chronic kidney injury models.
  • To summarize findings from a clinical study of an ASK1 inhibitor in diabetic kidney disease.

Main Methods:

  • Review of experimental studies using Ask1 gene-deficient mice.
  • Analysis of studies employing selective ASK1 inhibitors in various kidney disease models.
  • Examination of a clinical trial evaluating an ASK1 inhibitor in patients with diabetic kidney disease.

Main Results:

  • ASK1 blockade prevented cell injury, inflammation, fibrosis, albuminuria, and renal dysfunction in animal models.
  • Preclinical evidence supports ASK1 as a viable therapeutic target for kidney diseases.
  • An ASK1 inhibitor is currently under clinical investigation for moderate to advanced diabetic kidney disease.

Conclusions:

  • ASK1 inhibition represents a promising therapeutic strategy for acute and chronic kidney diseases.
  • Targeting ASK1 offers a potentially safer approach than directly inhibiting p38 MAPK or JNK.
  • Clinical evaluation of ASK1 inhibitors in diabetic kidney disease is warranted based on strong preclinical data.
Keywords:
acute renal injuryapoptosis signal-regulating kinase 1 (ASK1)c-Jun N-terminal kinase (JNK)diabetic kidney disease (DKD)glomerulonephritismitogen-activated protein kinase (MAPK)p38 MAPKrenal fibrosis

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