Kidney Week

Abstract: FR-PO924

TAZ Plays an Important Role in Maintenance of Podocyte Viability

Session Information

• Development, Stem Cells, Regenerative Medicine - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Development, Stem Cells, and Regenerative Medicine

• 501 Development, Stem Cells, and Regenerative Medicine: Basic

Authors

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

Jianchun Chen,

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

Raymond C. Harris,

Background

TAZ (also known as WWTR1), a paralogue of YAP, is an important nuclear effector of the Hippo signaling pathway. TAZ shares 45% amino acid identity with YAP and they share some redundant roles in some organ development, but they also differ in some functions. TAZ is highly expressed in kidney, especially in renal proximal tubule cells. TAZ global knockout causes early mortality in a subset of homozygous mice, while bilateral kidney cysts and a pulmonary emphysema-like phenotype presented in the surviving adult mice. YAP is highly expressed in the nucleus of podocytes, and podocyte-specific deletion of YAP causes FSGS and progressive renal failure. The goal of these studies was to determine whether TAZ also plays a physiologic role in podocytes.

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 cultured 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). There was increased YAP expression and nuclear localization in the TAZ^podKO mice compared with TAZ^podWT mice. Glomeruli of TAZ^podKO mice had increased cleaved-caspase 3 and decreased Bcl2 expression. In cultured podocytes, silencing TAZ by siRNA altered cell morphology and F-actin distribution, up-regulated of cleaved-caspase 3 and inhibited Bcl2 expression.

Conclusion

This study demonstrates that TAZ expression plays an important role in maintenance of podocytes, which cannot be compensated by its paralogue YAP.

Funding

• NIDDK Support