Kidney Week

Abstract: PO1700

TAZ Is Important for Structural and Functional Integrity of Podocytes

Session Information

• Podocyte Pathobiology: Basic Science Studies and Animal Models
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Chen, Jianchun, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jianchun Chen, MD

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

Background

Podocyte is an important component of glomerular filtration barrier (GFB) . Maintenance of integrity of slit-diaphragm(SD) structure is critical for normal kidney function. Podocytes lost most epithelial cell tight junction components except for Zonula occludens-1 and -2 (ZO-1 and ZO-2). In podocytes, ZO-1 is an important binding partner of Neph1, and mice with podocyte-specific ZO-1 deletion showed significant growth retardation and severe proteinuria starting at 2 weeks of age, but the regulation of ZO-1 expression in podocytes are not clear. TAZ (transcriptional coactivator with PDZ-binding motif) and its paralog Yes-associated protein (YAP) are two crucial effectors of Hippo signaling pathway. Recent study has shown that podocyte-specific YAP deletion causes FSGS and progressive renal failure, but the potential role of TAZ in podocytes has not been studied.

Methods

Mice with podocyte-TAZ deletion (TAZ^podKO) were generated by crossing TAZ^flox/flox mice with podocin-Cre recombinase transgenic mice. Urinary albumin excretion and kidney histology and podocyte number per glomerulus were evaluated in TAZ^podKO and WT mice. Immunoblotting analysis of isolated glomerulus lysates of TAZ^podKO or TAZ^podWT mice were performed. In primary cultured mouse podocytes and immortalized mouse podocytes cell morphology and cell lysates were evaluated after silencing TAZ with specific siRNAs.

Results

41.7% of TAZ^podKO mice develop mild proteinuria at age of 3-4 weeks (n=36), with a urine albumin/creatinine ratio of 89.57 ± 12.67 vs 27.86 ± 1.55 (µg/mg, n=7). At 9 weeks of age, compared to TAZ^podWT mice, the glomeruli of TAZ^podKO mouse kidney had focal sclerosis and significant podocyte loss (WT1+ cells: 13.23 ± 0.699 vs. 17.85 ± 0.608 (n=13). Expression of Bcl2, ZO-1, ZO-2 and synaptopodin were decreased, but expression of cleaved-caspase 3 in the isolated glomeruli from TAZ^podKO mice compared with TAZ^podWT mice. In cultured podocytes, silencing TAZ by siRNA altered cell morphology and F-actin distribution, and downregulation of Bcl2, ZO-1, ZO-2 and synaptopodin expression and up-regulation of cleaved-caspase 3 expression.

Conclusion

This study demonstrates that TAZ expression plays an important role in regulating podocyte structural protein expression, which cannot be compensated by its paralogue YAP.

Funding

• NIDDK Support