Kidney Week

Abstract: SA-PO928

High Salt Intake Increases Baseline Peritoneal Transport Rate Through Local TonEBP Activation in Subtotal Nephrectomized Mice

Session Information

• Dialysis: Peritoneal Dialysis - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 703 Dialysis: Peritoneal Dialysis

Authors

• Sun, Ting, Nagoya University Graduate School of Medicine, Nagoya, Japan

Ting Sun,

• Mizuno, Masashi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Masashi Mizuno,

• Suzuki, Yasuhiro, Nagoya University Graduate School of Medicine, Nagoya, Japan

Yasuhiro Suzuki,

• Tomita, Takako, Nagoya University Graduate School of Medicine, Nagoya, Japan

Takako Tomita,

• Sakata, Fumiko, Nagoya University Graduate School of Medicine, Nagoya, Japan

Fumiko Sakata,

• Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Shoichi Maruyama,

• Katsuno, Takayuki, Aichi Medical University, Nagakute, Aichi, Japan

Takayuki Katsuno,

• Kinashi, Hiroshi, Aichi Medical University, Nagakute, Aichi, Japan

Hiroshi Kinashi,

• Ito, Yasuhiko, Aichi Medical University, Nagakute, Aichi, Japan

Yasuhiko Ito,

Background

Baseline peritoneal solute transport rate (PSTR) measured by peritoneal equilibration test (PET) within 6 months after PD commencement varies between patients independently of PD therapy. Previously, we have reported a positive association between baseline D/P Cr and the number of peritoneal blood vessels, macrophages and IL-6-positive cells (2011,NDT). Besides, our recent work has shown that high salt intake promotes tissue inflammation in uremic mice (2017, Lab Invest). The present study aims to probe whether high salt intake causes pre-dialysis intraperitoneal inflammation and leads to high PSTR in subtotal nephrectomized mice.

Methods

Sham-operated (Sham) and subtotal nephrectomized (Nx) mice were randomly given tap water or 1% salt (NaCl)-containing water. After 8 weeks, 4.25% glucose-based PET was performed to evaluate peritoneal function. In another experiment, overexpressed intraperitoneal IL-6 was functionally blocked by MR16-1 to examine the role of IL-6 in this process. Human mesothelial cell line Met5A was used for in vitro studies.

Results

A significant elevation of D/P Cr and a decrease of D/D0 glucose were observed in Nx+salt group. There was also enhanced angiogenesis and macrophage infiltration in the peritoneum of Nx+salt mice, along with elevated VEGF-A and MCP-1 concentration in the dialysate. Compared to Nx+water group, the increased concentration of effluent but not serum IL-6 suggested a strong local production in Nx+salt group. Blockade of IL-6 signaling by MR16-1 alleviated angiogenesis and macrophage infiltration in Nx+salt mice and rescued peritoneal transport function. In cultured human mesothelial cells, 40mM additional NaCl in the medium could significantly upregulate the expression of IL-6, as well as VEGF-A and -C, companied by an increased expression and nuclear translocation of TonEBP, an osmolality-sensing transcription factor. Knockdown of TonEBP by siRNA could lower such overexpression caused by high tonicity. Notably, peritoneal expression of TonEBP in Nx+salt group also showed an upregulation, indicating a key role of it in higher peritoneal transport status.

Conclusion

These findings suggest that high salt intake under uremic status could increase peritoneal transport rate via local TonEBP activation.

Funding

• Commercial Support – CHUGAI PHARMACEUTICAL CO.,LTD.