Abstract: FR-PO689
Increased Glomerular Elasticity Corresponds to Podocyte Injury and Loss in Alport Mice
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Miller, R. Tyler, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Liu, Zhenan, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Yoon, Joonho, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Bruggeman, Leslie A., Case Western Reserve University, Cleveland, Ohio, United States
- Xing, Chao, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Sathe, Adwait, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Janmey, Paul A., University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Henderson, Joel M., Boston University School of Medicine, Boston, Massachusetts, United States
- Chang, Audrey N., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Group or Team Name
- UT Southwestern Medical Center
Background
In primary glomerular renal disease, podocyte injury leads proteinuria, hematuria, and later fibrosis with loss of tubular function. Podocyte injury causes disruption of cytoskeletal architecture with loss of foot processes and podocyte loss. We used Col4a3 KO Alport model mice to understand early steps in podocyte injury and loss.
Methods
Col4a3 knockout (KO) mice (Alport Syndrome model, C57bl/6j) are born with normal renal function and progress to ESRD by 7 months. Activation of the unfolded protein response (UPR) in podocytes, attributed to accumulation of misfolded collagen heterotrimers, is a potential cause of podocyte injury in Alport nephropathy. We studied the structural and biophysical properties of podocytes in glomeruli from WT, KO, and tauroursodeoxycholic acid (TUDCA)-treated KO mice using microindentation, confocal microscopy, transmission EM, and bulk- and single-cell RNAseq to evaluate gene expression differences. We tested the hypotheses that 1) glomerular biophysical properties reflect podocyte injury and reduced cell number and 2) alleviation of the UPR reduces podocyte injury and preserves podocyte cell number and glomerular function.
Results
Increased glomerular deformability precedes proteinuria and increased serum creatinine that corresponds to increased podocyte loss that is associated with reduced podocyte adhesion. This period is followed by glomerular stiffening, reduced renal function, proteinuria, and fibrosis. Treatment with TUDCA reduced podocyte loss, normalized glomerular elasticity, and slowed progression of renal disease by functional and morphologic criteria. Bulk RNAseq and qRT-PCR showed patterns of fibrosis and inflammation that intensified with glomerular stiffening, proteinuria and reduced renal function, and that was reduced by TUDCA. scRNAseq of podocytes early in the course of disease before significant podocyte loss demonstrated injury pathway activation, with compensation by podocytes to resist injury and enhance cytoskeletal structure and adhesion.
Conclusion
Significant podocyte injury and loss occur before proteinuria and renal function deteriorates and fibrosis is a late event. Therapeutic efforts might be most effective when directed at early podocyte injury and loss.
Funding
- NIDDK Support