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Abstract: SA-PO1004

Deletion of IRE1α Exacerbates Diabetic Nephropathy in Mice

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Cybulsky, Andrey V., McGill University, Montreal, Quebec, Canada
  • Papillon, Joan, McGill University, Montreal, Quebec, Canada
  • Guillemette, Julie, McGill University, Montreal, Quebec, Canada
  • Navarro-Betancourt, José R., McGill University, Montreal, Quebec, Canada
  • Chung, Chen-Fang, McGill University, Montreal, Quebec, Canada
  • Iwawaki, Takao, Kanazawa Medical University, Uchinada, Japan
  • Fantus, Ivan George, McGill University, Montreal, Quebec, Canada
Background

Protein misfolding in the endoplasmic reticulum (ER) of podocytes is an important contributor to the pathogenesis of glomerular diseases. ER protein misfolding activates a compensatory signaling network called the unfolded protein response (UPR). Deletion of the UPR transducer, inositol-requiring enzyme 1α (IRE1α) in mouse podocytes leads to podocyte injury and albuminuria in aging, and exacerbates injury in glomerulonephritis. This study addresses the role of the UPR and IRE1α in diabetic nephropathy.

Methods

We studied mice with podocyte-specific deletion/knockout (KO) of IRE1α. Hyperglycemia was induced in male mice (age 3-4 months) with streptozotocin.

Results

Streptozotocin-treated control and IRE1α KO mice developed comparable hyperglycemia (diabetes). Diabetes caused progressive albuminuria in control mice (3.7 mg/mg creatinine at 6 months) that was exacerbated in IRE1α KO mice (8.5 mg/mg creatinine; P<0.01). Albuminuria was ~1 mg/mg creatinine in non-diabetic groups (4-13 mice/group). Compared to diabetic controls, diabetic IRE1α KO mice showed a reduction in podocytes (WT1-positive cells; P<0.0001) and synaptopodin (P<0.05). Both non-diabetic and diabetic IRE1α KO mice showed increased glomerular matrix expansion compared to their respective controls. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; changes included widening of foot processes and glomerular basement membrane, microvesiculation of podocyte plasma membranes, and markedly dilated ER and mitochondrial architectural damage in podocytes. Activation of the UPR (increased glomerular ER chaperones) and autophagy (increased LC3-II, decreased p62) was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD (Nephroseq) database demonstrated activation of pathways and gene ontology categories, as well as induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy.

Conclusion

Mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy. This was associated with an attenuation of the glomerular UPR and autophagy, implying a protective mechanism mediated via IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.

Funding

  • Government Support – Non-U.S.