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RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase

Mitsuru Imamura1, Jong-Seok Moon1,2, Kuei-Pin Chung1

  • 1Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

JCI Insight
|February 9, 2018
PubMed

Insights

Receptor-interacting protein kinase-3 (RIPK3) drives kidney fibrosis independently of necroptosis. Inhibiting RIPK3 or its downstream AKT-ATP citrate lyase pathway offers a novel therapeutic strategy for chronic kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pathology

Background:

  • Renal fibrosis is a key driver of chronic kidney disease (CKD) progression.
  • Receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, is implicated in kidney injury.
  • Understanding RIPK3's role in fibrosis is crucial for developing new CKD treatments.

Purpose of the Study:

  • To investigate the role of RIPK3 in kidney fibrosis.
  • To elucidate the molecular mechanisms by which RIPK3 promotes renal fibrogenesis.
  • To evaluate RIPK3 and its downstream targets as potential therapeutic targets for CKD.

Main Methods:

  • Utilized mouse models of unilateral ureteral obstruction (UUO) and adenine diet (AD) to induce kidney fibrosis.
  • Employed RIPK3 and mixed-lineage kinase domain-like protein (MLKL) knockout mice to assess their roles in fibrosis.
  • Investigated the AKT-ATP citrate lyase (ACL) pathway activation in response to TGF-β1 in fibroblasts and its modulation by RIPK3.

Main Results:

  • RIPK3 expression was increased in fibrotic kidneys in UUO and AD models.
  • RIPK3 deficiency protected against kidney fibrosis and improved kidney function, while MLKL deficiency did not.
  • RIPK3 promotes fibrogenesis via AKT-dependent activation of ACL, independent of MLKL-mediated necroptosis.
  • Inhibition of AKT or ACL reduced extracellular matrix production and myofibroblast differentiation.
  • Pharmacological ACL inhibition ameliorated UUO-induced kidney fibrosis.

Conclusions:

  • RIPK3 promotes kidney fibrosis through a novel pathway involving AKT and ACL, independent of necroptosis.
  • Targeting RIPK3 or its downstream AKT-ACL axis presents a promising therapeutic strategy for managing kidney fibrosis in CKD.
  • RIPK3 expression is dysregulated in human CKD kidneys, supporting its clinical relevance.
Keywords:
Cell BiologyFibrosisMouse modelsNephrologyUrology

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