Abstract: TH-PO771
Regulation of Podocyte Adhesion by SEL1L-HRD1 ERAD via Integrin
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
Authors
- Wei, Xiaoqiong, University of Michigan, Ann Arbor, Michigan, United States
- Lu, You, University of Michigan, Ann Arbor, Michigan, United States
- Qi, Ling, University of Michigan, Ann Arbor, Michigan, United States
Background
Podocytes are specialized epithelial cells crucial for the kidney glomerular filtration barrier. They form interdigitating foot processes with neighboring podocytes in the kidney glomerulus to filter the blood. Adhesion of podocytes to glomerular basement membrane (GBM) is key to the formation of foot process and filtration function. Impairment of this process causes podocyte detachment, proteinuria and glomerulosclerosis in humans. While homeostasis in the endoplasmic reticulum (ER) has been generally recognized as important for cellular function, our understanding of ER homeostasis in podocytes remains unclear. Endoplasmic reticulum-associated degradation (ERAD) is the primary mechanism for the clearance of misfolded ER proteins by cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex represents the most conserved ERAD pathway. However, the role of SEL1L-HRD1 ERAD in podocyte function remains poorly understood.
Methods
The podocyte-specific SEL1L-deficient mice were generated. Mouse body weight and survival curve were recorded. Urine samples from mice at 1, 3, and 5 weeks of age were collected to assess the abundance of albumin and WT1. Kidneys from wild-type (WT) and SEL1L-deficient mice were collected for ultrastructure observation by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), the abundance and cellular location of the integrin subunit ITGA3 by immunofluorescence staining and western blot.
Results
Compared with WT mice, SEL1L-deficient mice showed lower body weight and premature renal failure with a median lifespan of 14 weeks. More albumin and detached podocytes were observed in SEL1L-deficient mice. Moreover, SEL1L-deficient mice showed damaged glomeruli and severe foot process effacement based on SEM and TEM. In terms of molecular mechanism, ITGA3, an important podocyte adhesion receptor, was accumulated in the ER, not exit to podocyte membrane, in the absence of SEL1L-ERAD.
Conclusion
Our data demonstrate SEL1L-ERAD regulates podocyte attachment on the glomerular basement membrane via degrading misfolded integrin subunit, ITGA3.
Funding
- NIDDK Support