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Abstract: PO1700

TAZ Is Important for Structural and Functional Integrity of Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Chen, Jianchun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
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 (TAZpodKO) were generated by crossing TAZflox/flox mice with podocin-Cre recombinase transgenic mice. Urinary albumin excretion and kidney histology and podocyte number per glomerulus were evaluated in TAZpodKO and WT mice. Immunoblotting analysis of isolated glomerulus lysates of TAZpodKO or TAZpodWT 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 TAZpodKO 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 TAZpodWT mice, the glomeruli of TAZpodKO 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 TAZpodKO mice compared with TAZpodWT 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