Abstract: SA-PO1031
The Inhibitory Role of ERK1 Signaling in Renal Sodium Handling and Blood Pressure Through Affecting Sodium Chloride Co-Transporter
Session Information
- Fluid and Electrolytes: Basic - II
October 27, 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
- Chen, Shan, Emory University, Atlanta, Georgia, United States
- Feng, Xiuyan, LSU Shreveport , Shreveport, Louisiana, United States
- Xu, Yixiao, Emory University, Atlanta, Georgia, United States
- Wang, Yunman, Emory University, Atlanta, Georgia, United States
- Xiao, Jia, Emory University, Atlanta, Georgia, United States
- Chen, Xinxin, Emory University, Atlanta, Georgia, United States
- Li, Ruidian, Emory University, Atlanta, Georgia, United States
- Shen, Saier, Emory University, Atlanta, Georgia, United States
- Cai, Hui, Emory University, Atlanta, Georgia, United States
Background
Sodium chloride cotransporter (NCC) plays a key role in regulating blood pressure and electrolyte homeostasis. Our previous study showed that WNK4 inhibits NCC by activating ERK1/2 signaling. Although ERK1 and ERK2 share 80% amino acid sequences, roles of ERK1 and ERK2 were reported to be different. Our preliminary studies showed that NCC was decreased in the inducible renal tubular specific ERK2 knockout (KO) mice, suggesting that the ERK1 and ERK2 pathways modulate NCC differently. Thus, we hypothesized that ERK1 signaling pathway plays an inhibitory role in regulating renal sodium excretion and blood pressure through NCC.
Methods
ERK1 global KO mice, western blot analysis, cell culture, siRNA knock-down, metabolic cage study, and tail-cuff blood pressure (BP) measurement were used in this study.
Results
To determine whether ERK1 involves in NCC regulation in vivo, we first did western blot experiments. We found that NCC abundance was increased in ERK1 KO mice. To investigate whether ERK1 affects NCC protein expression in vitro, we did ERK1 siRNA knock-down experiments in Cos-7 cells cotransfected with NCC and siRNA ERK1. We found that ERK1 knockdown increased NCC protein expression. To explore whether ERK1 signaling pathway involves in sodium excretion, we collected 24-h urine using metabolic cage. We found that 24-h urinary sodium excretion / body weight was significantly lower in ERK1 KO mice compared to WT control mice (0.0088 ± 0.0009 vs 0.0107± 0.0014 mmol/g, n=6, p < 0.05). To further investigate the role of ERK1 signaling on NCC function, we did metabolic cage study in ERK1 KO mice administrated with either control vehicle or hydrochlorothiazide (HCTZ), a specific NCC inhibitor. We found that ERK 1 mice have more exaggerated response to HCTZ treatment (25mg/kg wt, i.p.) compared to WT mice in urinary sodium excretion (0.49 ± 0.10 vs 0.28 ± 0.14 mmol, p < 0.05, n=3), indicating a higher NCC activity in ERK 1 KO mice. Furthermore, we found that systolic BP was higher in ERK1 KO mice than that in WT mice (127.2 ± 4.7 vs 112.9 ± 9.8, n= 4, p < 0.05) by tail-cuff method.
Conclusion
Taken all above data together, we concluded that ERK1 signaling pathway plays an inhibitory role in NCC function and NCC protein expression, which affects renal sodium handling and blood pressure.
Funding
- Veterans Affairs Support