Abstract: SA-PO1085

A Critical Role of Angiotensin II Type 1 Receptor Binding Molecule in Hypertension in a CKD Model

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Kobayashi, Ryu, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan
  • Wakui, Hiromichi, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan
  • Uneda, Kazushi, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan
  • Haruhara, Kotaro, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan
  • Nishiyama, Akira, Kagawa University Medical School, Kita-Gun, Japan
  • Tanabe, Katsuyuki, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
  • Maeshima, Yohei, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan
  • Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan
Background

The renin-angiotensin system plays a key role in the maintenance of cardiovascular and renal homeostasis, principally via appropriate activation of Ang II type 1 receptor (AT1R). We previously identified an AT1R-associated protein (ATRAP/Agtrap), which promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. We hypothesized that dysregulation of renal ATRAP expression and subsequent AT1R hyperactivation contributes to development of hypertension that occurs as a complication of the remnant kidney CKD model.

Methods

We compared changes in endogenous ATRAP expression and blood pressure between 129/Sv and C57BL/6 mice using the remnant kidney model after 5/6 nephrectomy. We also examined the effect of ATRAP deficiency in C57BL/6 mice (with a hypertension-resistant strain background) on blood pressure regulation after 5/6 nephrectomy. To more directly examine the mechanism of hypertension, ATRAP-knockout (KO) mice were treated with the soluble TNF-α receptor, etanercept, or with vehicle after 5/6 nephrectomy.

Results

We first examined the effect of 5/6 nephrectomy on endogenous ATRAP expression in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice that underwent 5/6 nephrectomy showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of remnant kidney CKD model-related hypertension. To investigate this, we performed 5/6 nephrectomy in ATRAP-knockout (KO) mice on the hypertension-resistant C57BL/6 background. ATRAP-KO mice that underwent 5/6 nephrectomy showed hypertension with increased plasma volume. Moreover, in ATRAP-KO mice compared with wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane AT1R in the kidneys.

Conclusion

These results indicate that renal ATRAP downregulation is involved in onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in CKD.