Kidney Week

Abstract: SA-PO849

TNF-α Blockade Attenuates Hypertension and Renal Expression of the Epithelial Sodium Channel Α-Subunit in the Remnant Kidney CKD Model Using ATRAP Deficient Mice

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Kobayashi, Ryu, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan

Ryu Kobayashi,

• Wakui, Hiromichi, Yokohama City University, Yokohama, Japan

Hiromichi Wakui,

• Azushima, Kengo, Yokohama City University, Yokohama, Japan

Kengo Azushima,

• Uneda, Kazushi, Yokohama City University, Yokohama, Japan

Kazushi Uneda,

• Ohki, Kohji, Yokohama City University School of Medicine, Yokohama, Japan

Kohji Ohki,

• Kinguchi, Sho, Yokohama City University, Yokohama, Japan

Sho Kinguchi,

• Yamaji, Takahiro, Yokohama city unversity, Yokohama, Japan

Takahiro Yamaji,

• Urate, Shingo, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan

Shingo Urate,

• Toya, Yoshiyuki, Yokohama City University, Yokohama, Japan

Yoshiyuki Toya,

• Tamura, Kouichi, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, KANAGAWA, Japan

Kouichi Tamura,

Background

We previously identified an angiotensin type 1 receptor (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 plays a critical role in development of hypertension in remnant kidney chronic kidney disease (CKD) model.

Methods

First, 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. Second, we examined the effect of ATRAP deficiency in C57BL/6 mice (with a hypertension-resistant strain background) on blood pressure regulation after 5/6 nephrectomy. Third, ATRAP-knockout (KO) mice were treated with the soluble TNF-α receptor, etanercept, or with vehicle after 5/6 nephrectomy.

Results

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. Next, we performed 5/6 nephrectomy in ATRAP-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 (αENaC) and tumor necrosis factor-α (TNF-α) was significantly enhanced, concomitant with increased plasma membrane AT1R in the kidneys. TNF-α inhibition with etanercept significantly suppressed 5/6 nephrectomy-induced blood pressure elevation in ATRAP-KO mice. Furthermore, renal expression of αENaC protein was significantly decreased in ATRAP-KO mice treated with etanercept, compared with vehicle, at 4 weeks after 5/6 nephrectomy.

Conclusion

These results indicate that promotion of primary sodium reabsorption in the renal tubules of the remnant kidney via activation of the AT1R-TNF-α-αENaC axis is a plausible mechanism for the increased circulating plasma volume observed in ATRAP-KO mice after 5/6 nephrectomy.