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RIPK3 exhibits a U-shaped dose-response in AKI-to-CKD progression: Optimal therapeutic window and the TGF-β1-HMGB1

Cuilan Liu1, Ziyi Yan2, Wen Yang1

  • 1The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, 075000, China.

Biochemical and Biophysical Research Communications
|February 4, 2026
PubMed

Insights

Acute kidney injury (AKI) survivors face chronic kidney disease (CKD) risk. Targeting RIPK3 (receptor-interacting protein kinase 3) activity at specific times, not just early, may prevent AKI-to-CKD progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Acute kidney injury (AKI) survivors have an increased risk of progressing to chronic kidney disease (CKD).
  • The precise role of RIPK3 (receptor-interacting protein kinase 3) in AKI-to-CKD transition and the optimal timing for therapeutic intervention remain incompletely understood.
  • Understanding RIPK3's stage-specific functions is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the temporal expression and upstream regulation of RIPK3 following renal ischemia-reperfusion injury (IRI).
  • To evaluate the impact of RIPK3 deficiency and pharmacological inhibition at different time points on AKI progression to CKD.
  • To elucidate the molecular mechanisms linking RIPK3, TGF-β1, and HMGB1 in kidney injury and fibrosis.

Main Methods:

  • Utilized a bilateral renal IRI mouse model with varying RIPK3 gene dosages (Ripk3+/+, Ripk3+/-, Ripk3-/-).
  • Administered the RIPK3 inhibitor GSK872 at different time windows (day 0, 7, or 14 post-injury).
  • Assessed renal function, histology, survival, and molecular markers including RIPK3 activity, TGF-β1, Smad3, and HMGB1.

Main Results:

  • RIPK3 and phosphorylated RIPK3 levels increased post-AKI and persisted for 28 days.
  • A U-shaped dose-response for RIPK3 was observed, with Ripk3+/- mice exhibiting less injury and fibrosis than wild-type or Ripk3-/- mice.
  • Initiating RIPK3 inhibition with GSK872 on day 7 significantly improved outcomes compared to earlier or later treatment, correlating with reduced sustained inflammation.
  • Identified a positive feedback loop where TGF-β1 induces RIPK3 via Smad3, and RIPK3-mediated injury promotes HMGB1 release, further activating TGF-β1/Smad3 signaling.

Conclusions:

  • RIPK3 plays a complex, dose-dependent role in AKI-to-CKD progression.
  • Therapeutic targeting of RIPK3 requires careful consideration of intervention timing, with subacute treatment showing greater efficacy.
  • Modulating RIPK3 activity in a stage- and dose-aware manner presents a promising strategy to prevent the transition from AKI to CKD.
Keywords:
Acute kidney injuryChronic kidney diseaseHMGB1NecroptosisPositive feedback loopRIPK3Renal fibrosisTGF-β1Therapeutic window

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