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Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in

Thati Madhusudhan1, Hongjie Wang2, Wei Dong1

  • 1Institute of Clinical Chemistry and Pathobiochemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg 39120, Germany.

Nature Communications
|March 11, 2015
PubMed

Insights

Impaired endoplasmic reticulum (ER) stress signaling in kidney podocytes contributes to diabetic nephropathy (DN). Disruption of the insulin receptor-PI3K-XBP1 pathway compromises podocyte function in DN.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Endocrinology

Background:

  • Diabetic nephropathy (DN) involves endoplasmic reticulum (ER) stress in kidney podocytes.
  • The precise mechanisms of ER signaling dysfunction in DN remain unclear.

Purpose of the Study:

  • To investigate the role of spliced X-box binding protein-1 (sXBP1) signaling in podocyte function during DN.
  • To elucidate the link between insulin signaling and ER stress in DN pathogenesis.

Main Methods:

  • Utilized mouse models with podocyte-specific genetic alterations (XBP1 ablation, ATF6 induction, insulin receptor/PI3K subunit deficiency).
  • Analyzed nuclear translocation of sXBP1 and expression of ATF6 and CHOP.
  • Examined interactions between sXBP1 and PI3K regulatory subunits (p85α/β) in murine and human DN samples.

Main Results:

  • Nuclear translocation of sXBP1 is impaired in DN, leading to increased ATF6 and CHOP.
  • Podocyte-specific XBP1 deficiency or ATF6 overexpression exacerbates DN.
  • Impaired insulin signaling (via insulin receptor, PI3K p85α/β) disrupts sXBP1 translocation and worsens DN.
  • sXBP1 interaction with p85α/β is reduced in human DN glomeruli.

Conclusions:

  • The insulin receptor-PI3K-sXBP1 pathway is crucial for maintaining podocyte homeostasis.
  • Disruption of this pathway contributes to podocyte dysfunction and DN progression.
  • Targeting this pathway may offer therapeutic strategies for DN.

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