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

Nat Commun. 2015 Mar 10;6:6496. doi: 10.1038/ncomms7496.

Abstract

Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85α or p85β impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85α and p85β is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / deficiency
  • Activating Transcription Factor 6 / genetics*
  • Animals
  • Class Ia Phosphatidylinositol 3-Kinase / deficiency
  • Class Ia Phosphatidylinositol 3-Kinase / genetics*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Databases, Factual
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / chemically induced
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Regulation
  • Humans
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Receptor, Insulin / deficiency
  • Receptor, Insulin / genetics
  • Regulatory Factor X Transcription Factors
  • Signal Transduction
  • Streptozocin
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • X-Box Binding Protein 1

Substances

  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • DNA-Binding Proteins
  • Ddit3 protein, mouse
  • Insulin
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Transcription Factor CHOP
  • Streptozocin
  • Class Ia Phosphatidylinositol 3-Kinase
  • Receptor, Insulin