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PP2A-ERK-PPAR-α/PGC-1α Axis Drives Tubular Lipotoxicity and Mitochondrial Dysfunction in Nephron-Sparing

Haoxun Zhang1,2,3, Guoling Zhang1,2,3, Bowen Wang1,3

  • 1Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Antioxidants & Redox Signaling
|June 2, 2026
PubMed
Abstract

Insights

Nephron-sparing surgery causes kidney injury by disrupting tubular energy metabolism via protein phosphatase 2A (PP2A) and ERK-PPAR-α/PGC-1α signaling, highlighting metabolic resilience as a therapeutic target.

Area of Science:

  • Renal physiology and pathophysiology
  • Cellular metabolism and mitochondrial function
  • Surgical injury mechanisms

Background:

  • Nephron-sparing surgery (NSS) is linked to acute kidney injury (AKI), potentially accelerating chronic kidney disease.
  • Mechanisms of NSS-related injury (NRI), particularly metabolic reprogramming independent of ischemia, are not fully understood.
  • Proximal tubular cells are crucial for kidney function and susceptible to metabolic stress.

Purpose of the Study:

  • To elucidate the mechanisms of lipid metabolic dysregulation and mitochondrial dysfunction in NRI.
  • To investigate the role of surgical stress in reprogramming proximal tubular energy metabolism.
  • To identify potential therapeutic targets for mitigating NRI.

Main Methods:

  • Clinical cohort analysis of prolonged warm ischemia time and postoperative AKI.
  • Analysis of proximal tubular cells in human and experimental NRI models.
  • Experimental modulation of protein phosphatase 2A (PP2A) and extracellular signal-regulated kinase (ERK)-PPAR-α signaling.
  • Single-cell and cell-type-resolved analyses to pinpoint affected tubular subpopulations.

Main Results:

  • Prolonged warm ischemia time correlated with increased postoperative AKI.
  • NRI exhibited suppressed fatty acid oxidation, increased lipid accumulation, and mitochondrial dysfunction in proximal tubules.
  • These metabolic changes were linked to increased PP2A activity, reduced ERK phosphorylation, and diminished PPAR-α/PGC-1α signaling.
  • Modulating PP2A or restoring ERK-dependent PPAR-α signaling partially ameliorated kidney injury.

Conclusions:

  • PP2A-dependent suppression of ERK-PPAR-α/PGC-1α signaling is a key mechanism in proximal tubular metabolic failure during NRI.
  • Surgical stress disrupts lipid metabolism through a pathway distinct from classical ischemic injury.
  • Enhancing tubular metabolic resilience presents a promising therapeutic strategy for NRI.
Keywords:
PPAR-αacute kidney injurylipotoxicitymitochondrial dysfunctionprotein phosphatase 2Asignaling

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