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PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling

Qian Yuan1, Ben Tang1, Yaru Xie1

  • 1Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Death and Differentiation
|March 11, 2025
PubMed

Insights

PR domain-containing 16 (PRDM16) is crucial for podocyte health and insulin signaling. Restoring PRDM16 protects against podocyte injury and kidney disease, offering a new therapeutic target.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Diabetology

Background:

  • Podocytopathies involve impaired glucose uptake due to suppressed insulin receptor signaling.
  • Identifying therapeutic targets for podocyte insulin signaling is clinically significant.

Purpose of the Study:

  • To investigate the role of PR domain-containing 16 (PRDM16) in podocyte insulin receptor signaling and podocyte injury.
  • To elucidate the underlying molecular mechanisms of PRDM16 in kidney disease.

Main Methods:

  • Observed PRDM16 expression in human and mouse podocyte injury models.
  • Utilized podocyte-specific Prdm16 deletion and lentiviral PRDM16 delivery in diabetic nephropathy (DN) and adriamycin (ADR) nephropathy mouse models.
  • Investigated the effects of PRDM16 on glucose uptake, insulin receptor signaling, NEDD4L transcription, IKKβ stability, and IRS-1 phosphorylation/degradation.
  • Assessed the therapeutic potential of exogenous NEDD4L.

Main Results:

  • PRDM16 expression was significantly reduced in damaged podocytes.
  • Podocyte-specific Prdm16 deletion exacerbated kidney injury in DN mice.
  • Exogenous PRDM16 ameliorated pathological changes in DN and ADR nephropathy mice.
  • PRDM16 deficiency impaired podocyte glucose uptake by inhibiting insulin receptor signaling.
  • PRDM16 loss downregulated NEDD4L, increasing IKKβ stability and IRS-1 degradation.
  • Exogenous NEDD4L reduced podocyte injury and ADR nephropathy.

Conclusions:

  • PRDM16 plays a vital role in maintaining podocyte insulin receptor signaling and preventing podocyte injury.
  • PRDM16 acts by regulating NEDD4L transcription, thereby controlling IKKβ and IRS-1 stability.
  • PRDM16 represents a potential therapeutic target for podocytopathies and related kidney diseases.

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