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Abstract: SA-PO329

Functional Impact of Proximal Tubule ATRAP in Blood Pressure Regulation

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Kinguchi, Sho, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Azushima, Kengo, Duke-NUS Medical School, Singapore, Singapore
  • Haruhara, Kotaro, The Jikei University School of Medcine, South Yarra, Victoria, Australia
  • Yamaji, Takahiro, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Yamada, Takayuki, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Kobayashi, Ryu, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Fujikawa, Tetsuya, Yokohama National University, Yokohama, KANAGAWA, Japan
  • Ohki, Kohji, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  • Wakui, Hiromichi, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Background

The angiotensin II (Ang II) receptor (AT1R)-associated protein (ATRAP) inhibits pathological activation of AT1R signaling in response to certain stimuli. We showed that systemic ATRAP knockout mice exhibits the exacerbation of Ang II-mediated hypertension via hyperactivation of distal tubule AT1R-ENaC pathway (Ohsawa Kid Int 2014; Kobayashi Kid Int 2017). Although ATRAP is also expressed abundantly in renal proximal tubules, little is known about a functional impact of proximal tubule ATRAP in blood pressure (BP) regulation in response to pathological stimuli.

Methods

We created proximal tubule-specific ATRAP knockout (PT-KO) mice using the Cre/loxP system with Pepck-Cre, and examined a functional role of proximal tubule ATRAP in angiotensin-mediated hypertension. For chronic Ang II stimulation experiments, Ang II (600 or 1000 ng/kg per minute) was infused subcutaneously in male WT and PT-KO mice (9–12 weeks old) for 14 days using an osmotic minipump (model 2002; ALZET).

Results

The ATRAP mRNA expression was decreased by ≈80% in renal proximal tubules of PT-KO mice compared with wild-type (WT) mice. The BP of PT-KO mice was comparable with that of WT mice at baseline. Moreover, in telemetry analysis, the 24-hour mean systolic BP was significantly and similarly increased in response to 2 weeks of Ang II infusion (1000 ng/kg per minute) in both PT-KO and WT mice (Ang II–infused PT-KO versus Ang II–infused WT mice, 2-way repeated measures ANOVA, F=0.04280, P=0.8407). Ang II infusion (1000 ng/kg per minute) for 2 weeks also significantly increased 24-hour mean systolic BP, not only in the light period but also in the dark period and to the same extent in both types of mice. The degrees of cardiac hypertrophy and albuminuria under Ang II -mediated hypertension were also similar in PT-KO and WT mice. In addition, the results of metabolic cage analysis showed that cumulative sodium balance during 2 weeks of Ang II infusion was comparable for PT-KO and WT mice.

Conclusion

Proximal tubule-specific down-regulation of ATRAP did not affect the Ang II-mediated hypertension in vivo. Since ATRAP is broadly expressed along renal tubules from proximal to distal tubules, proximal tubule ATRAP would be suggested to have a distinct function other than BP modulation in response to pathological stimuli.