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CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM

Jingfang Chen1,2,3,4, Dongwei Liu1,3,4, Lei Lei2

  • 1Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Research Institute of Nephrology, Zhengzhou University, Traditional Chinese Medicine Integrated Department of Nephrology，the First Affiliated Hospital of Zhengzhou University, Henan Province Research Center for Kidney Disease，the First Affiliated Hospital of Zhengzhou University, Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 11, 2025
PubMed

Insights

Diabetic nephropathy (DN) involves ferroptosis and mitochondria-associated endoplasmic reticulum membrane (MAM) damage. Canopy FGF signaling regulator 2 (CNPY2) exacerbates DN by promoting ferroptosis and MAM disruption via the PERK/ATF4/CHAC1 pathway.

Area of Science:

  • Cell Biology
  • Nephrology
  • Molecular Medicine

Background:

  • Ferroptosis is a key mechanism in diabetic nephropathy (DN) renal tubular injury.
  • Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is vital for cellular processes, but its role in DN is unclear.
  • Understanding the interplay between ferroptosis and MAM in DN is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the role of canopy FGF signaling regulator 2 (CNPY2) in ferroptosis and MAM regulation in diabetic nephropathy (DN).
  • To elucidate the underlying molecular mechanisms by which CNPY2 influences tubular injury in DN.

Main Methods:

  • Utilized db/db mouse models of diabetic nephropathy (DN).
  • Assessed the expression levels of CNPY2 in renal tubules.
  • Manipulated CNPY2 levels (downregulation and overexpression) to evaluate its impact on ferroptosis and MAM integrity.
  • Investigated the activation of the PERK/ATF4/CHAC1 signaling pathway.

Main Results:

  • CNPY2 was found to be upregulated in the renal tubules of DN models.
  • Downregulation of CNPY2 reduced ferroptosis and improved MAM integrity in DN.
  • CNPY2 overexpression worsened tubular injury by increasing ferroptosis and disrupting MAM formation.
  • CNPY2 was shown to activate the PERK/ATF4/CHAC1 pathway, promoting ferroptosis.

Conclusions:

  • CNPY2 plays a significant role in regulating ferroptosis and MAM integrity during diabetic nephropathy (DN) progression.
  • CNPY2 acts through the PERK/ATF4/CHAC1 signaling pathway to mediate ferroptosis and tubular injury in DN.
  • CNPY2 represents a potential therapeutic target for managing diabetic nephropathy (DN).
Keywords:
canopy FGF signaling regulator 2 (CNPY2)diabetic nephropathyendoplasmic reticulum (ER) stressferroptosismitochondria‐associated endoplasmic reticulum membrane (MAM)

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