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Abstract: TH-PO516

WNK1-SPAK-NCC Signaling Cascade Is Involved in Salt Sensitive Hypertension Induced by Aristolochic Acid Nephropathy

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Furusho, Taisuke, Tokyo Medical and Dental University, Tokyo, Japan
  • Sohara, Eisei, Tokyo Medical and Dental University, Tokyo, Japan
  • Mandai, Shintaro, Tokyo Medical and Dental University, Tokyo, Japan
  • Kikuchi, Hiroaki, Tokyo Medical and Dental University, Tokyo, Japan
  • Ando, Fumiaki, Tokyo Medical and Dental University, Tokyo, Japan
  • Zeniya, Moko, Tokyo Medical and Dental University, Tokyo, Japan
  • Mori, Takayasu, Tokyo Medical and Dental University, Tokyo, Japan
  • Nomura, Naohiro, Tokyo Medical and Dental University, Tokyo, Japan
  • Rai, Tatemitsu, Tokyo Medical and Dental University, Tokyo, Japan
  • Uchida, Shinichi, Tokyo Medical and Dental University, Tokyo, Japan
Background

Increased salt sensitivity is one of the major reasons for resistant hypertension in chronic kidney disease (CKD). Recent evidence suggests that not only reduced glomerular filtration but also aberrant sodium handling in renal tubules contribute to salt sensitivity. We previously demonstrated with-no-lysine kinase (WNK) - oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline-alanine-rich kinase (SPAK) - NaCl cotransporter (NCC) signaling cascade is essential for sodium handling in the distal nephron and its inappropriate activation leads to salt sensitive hypertension. However, WNK signaling in CKD has not been evaluated. In the present study, we investigated the role of WNK signaling in the development of salt sensitive hypertension induced by aristolochic acid nephropathy (AAN).

Methods

C57BL6/J or SPAK-/-mice were administered aristolochic acid I (AA-I) intraperitoneally twice a week for 6 weeks followed by 6 week disease development time. After the treatment, sodium transporter protein expression was assessed and the effect of high salt diet (HSD) on blood pressure was examined.

Results

AAN mice showed salt sensitive hypertension (systolic blood pressure after HSD, mean±SE: 112.5±2.6 mmHg in AAN and 102±1.0 mmHg in control, p<0.05, unpaired t test). In the AAN model, protein levels of WNK1, phosphorylated SPAK and phosphorylated NCC were significantly increased. Immunofluorescent study revealed increased expression of WNK1 and phosphorylated SPAK at distal convoluted tubules. Even after mice were fed a HSD, expression level of WNK signal remained increased. Increased phosphorylation of NCC was not observed in AA-I treated SPAK-/-mice, indicating NCC was activated through WNK1-SPAK phosphorylation cascade. As tumor necrosis factor α (TNFα) mRNA expression level was elevated in AAN mice kidney, we next evaluated the effect of TNFα on WNK signaling. We found that increased expression of WNK1, phosphorylated SPAK and phosphorylated NCC were attenuated in AAN mice treated with TNFα inhibitor etanercept.

Conclusion

NCC is activated through WNK1-SPAK signaling cascade in AAN mice and could contribute to salt sensitive hypertension. TNFα is involved in WNK signal activation induced by AAN.

Funding

  • Government Support - Non-U.S.