Kidney Week

Abstract: SA-PO1027

Involvement of CaSR, Claudin-14, and 16 in the Development of Hypermagnesiuria Associated with Tubulo-Interstitial Nephropathy

Session Information

• Fluid and Electrolytes: Basic - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Shimizu, Taisuke, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Taisuke Shimizu,

• Takayanagi, Kaori, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Kaori Takayanagi,

• Iwashita, Takatsugu, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Takatsugu Iwashita,

• Kurosawa, Akira, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Akira Kurosawa,

• Kitamura, Yuka, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Yuka Kitamura,

• Hara, Hiroaki, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Hiroaki Hara,

• Terao, Masaaki, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Masaaki Terao,

• Hida, Toru, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Toru Hida,

• Sano, Tatsuro, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Tatsuro Sano,

• Ogawa, Tomonari, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Tomonari Ogawa,

• Kanozawa, Koichi, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Koichi Kanozawa,

• Hasegawa, Hajime, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan

Hajime Hasegawa,

Background

Hypermagnesiuria is well known clinical feature of tubulo-interstitial nephropathy (TIN), and would be a diagnostic tool for TIN. We studied the changes in the expression of renal magnesium transporting molecules with the development of TIN in rats with unilateral ureter obstruction (UUO).

Methods

Left ureter of male SD rats was ligated, and the left kidney was sampled at day-0 (control), day-1 (early phase) and day-7 (late phase). Just before sampling, urine from the ureter-ligated kidney was collected by catheter insertion into the ureter. Immunohistochemistry, immunoblotting and RT-PCR were applied to this study.

Results

Fractional Mg excretion was significantly increased in the late phase but not in the early phase (FEMg: 3.13±0.81 at day-0, 4.72±0.54 at day-1, 10.7±0.81% at day-7). Immunohistochemistry and RT-PCR for fibrosis related gene indicated that TIN was developed in the late phase but not in the early phase. Expression of claudin-16, Mg reabsorption pathway in the thick ascending limb, was significantly decreased in the late phase but not in the early phase (100.2±2.9% at day-0, 90.3±6.3% at day-1, 36.4±1.6% at day-7). The results were confirmed by immunohistochemistry and immunoblotting. However, mRNA expression of TRPM6, Mg pathway of distal tubule, was significantly down-regulated even in the early phase (0.94±0.14% at day-0, 0.50±0.06% at day-1, 0.05±0.01% at day-7). Claudin-14 which is known to be an inhibitory regulator of claudin-16 was remarkably up-regulated. Because calcium sensing receptor (CaSR) signal is reported to function as an inhibitory regulator of claudin-14, we finally studied the expression of CaSR. CaSR mRNA was significantly down-regulated in the late phase (100.5±4.7 at day-0, 42.5±13.0 at day-1, 7.5±1.8% at day-7), and immunohistochemistry showed remarkable reduction of CaSR signal in the late phase.

Conclusion

Our findings may indicate that the characteristic hypermagnesiuria in TIN is principally caused by a dysfunction of magnesium reabsorption in the thick ascending limb of Henle resulting from a significant decrease in the claudin-16 expression. The down-regulation may be closely related to the development of TIN through CaSR-claudin-14-claudin-16 regulatory network.