RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase. Academic Article uri icon

Overview

abstract

  • Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-β1 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-β1-dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD.

publication date

  • February 8, 2018

Research

keywords

  • ATP Citrate (pro-S)-Lyase
  • Kidney
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Renal Insufficiency, Chronic

Identity

PubMed Central ID

  • PMC5821177

Scopus Document Identifier

  • 85052630538

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.94979

PubMed ID

  • 29415885

Additional Document Info

volume

  • 3

issue

  • 3