Abstract: FR-PO714
Tight Junction Protein Claudin-5 Protects the Podocytes After Injury in Proteinuric Renal Diseases
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
- Choudhury, Sonali, University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Behm, Christine V., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Riddle, Heather A.L., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Parnell, Stephen C., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Yu, Alan S.L., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
Background
Focal and segmental glomerulosclerosis (FSGS) is characterized by podocyte injury and impairment of the glomerular filtration barrier causing proteinuria, nephrotic syndrome and kidney failure. Podocytes respond to injury by foot process effacement and "fusion", with loss of slit diaphragms and replacement by tight junctions (TJ) between neighboring podocytes. Why TJs appear, and their role is unknown. Claudins are membrane proteins which are necessary to form TJs, and claudin-5 (Cldn5) is specifically expressed at the plasma membrane in adult podocytes and migrates to TJs upon injury.
Methods
To study the role of Cldn5, we generated Cldn5 homozygous Floxed (fl/fl) mice and crossed them to NPHS2-Cre mice to achieve podocyte-specific deletion of Cldn5 (Cre+). Glomeruli were isolated for Western blotting and immunofluorescence staining. Urine was collected from Cre+ mice and Cre- control littermates (N= 17-18 per group) at 5, 8, 15, 25, 35 and 45-weeks for measurement of albumin, by ELISA, and creatinine. Data was analyzed by linear mixed models with repeated measures over time.
Results
Podocyte-specific Cldn5 knockout mice (Cre+) were born at normal Mendelian ratios. Cldn5 was detected in podocytes of control mice by immunofluorescence and Western blotting and was absent from Cre+ mice indicating complete Cre excision. Cre+ mice developed increasing urine albumin/creatinine ratio (UACR) with age, compared to Cre- (P = 0.011), and male mice had increasing UACR with age compared to females (P = 0.015).
Conclusion
Cldn5 has a protective role in the glomerular filtration barrier at baseline. Since podocyte foot process effacement and TJ formation is common to all nephrotic disorders, Cldn5 may be critical in the adaptive response to FSGS and other podocytopathies. Ongoing studies are testing the role of Cldn5 in Adriamycin-induced podocyte injury.
Funding
- NIDDK Support