Abstract: TH-PO506
Inhibition of Polo-Like Kinase 1 (PLK1), a Cell Cycle Regulator, Prevents the Dysregulation of AQP2, AQP3, and NKCC2 in Obstructive Nephropathy
Session Information
- Fluid and Electrolytes: Basic - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid and Electrolytes
- 901 Fluid and Electrolytes: Basic
Authors
- Zhang, Yue, University of Utah/Nanjing Medical University, Nanjing, China
- Du, Yang, Nanjing Medical University, Nanjing, China
- Qian, Yun, Nanjing Medical University, Nanjing, China
- Guo, Yan, Nanjing Medical University, Nanjing, China
- Jiang, Mingzhu, Nanjing Medical University, Nanjing, China
- Chen, Shuang, Nanjing Medical University, Nanjing, China
- Ding, Guixia, Nanjng Medical University, Nanjing, China
- Huang, Songming, Nanjing Medical University, Nanjing, China
- Zhang, Aihua, Nanjing Medical University, Nanjing, China
- Jia, Zhanjun, Nanjing Medical University, Nanjing, China
Background
Obstructive kidney disease is accompanied by the dysregulation of water channels and sodium transporters, which could account for the water/sodium disorders after obstruction release. PLK1 is known as a key modulator of cell cycle progression. Recently, cell cycle-associated mechanism was shown to contribute to the renal tubular injury. Here we proposed that the inhibition of PLK1 may preserve the water channels and sodium transporters of renal tubules in obstructive nephropathy.
Methods
Male C57BL/6 mice were subjected to unilateral ureteral obstruction (UUO) surgery or sham operation. On day 4 and day 6 after UUO surgery, mice received i.p injection of specific PLK1 inhibitor BI6727(15mg/kg). On day 7 after UUO surgery, animals were sacrificed and kidney samples were collected for analysis.
Results
qRT-PCR analysis detected that the marked reduction of AQP2, AQP3, and NKCC2 (40-60%) in obstructed kidneys were largely normalized by BI6727 treatment at mRNA levels. By immunohistochemistry and Western blotting, we further confirmed that post therapy (day 4 and day 6 after kidney obstruction) by BI6727 entirely restored the reduction of AQP2 and NKCC2 proteins to the normal levels. Due to the known role of PGE2 cascade in regulating water channels and sodium transporters in obstructed kidney, we measured COX-1, COX-2 and mPGES-1 and observed 3-8 folds increments of these components of PGE2-generating cascade. However, BI6727 therapy did not affect the upregulation of COXs and mPGES-1, suggesting that inihbition of PLK1 prevserved AQP2, AQP3, and NKCC2 possibly through a prostaglandin-independent mechanism.
Conclusion
Inhibition of PLK1 restored the downregulation of AQP2, AQP3, and NKCC2 in obstructed kidneys, suggesting a novel role of tubular cell cycle progression in dysregulating water channels and sodium transporters independently of prostaglandin-associated mechanism in obstructive nephropathy.