Kidney Week

Abstract: FR-PO561

Lipopolysaccharide-Responsive Beige-Like Anchor Protein Is Essential for Sodium and Water Homeostasis

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Hara, Yu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Yu Hara, MD, PhD

• Ando, Fumiaki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Fumiaki Ando, MD, PhD

• Yanagawa, Hideki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Hideki Yanagawa, MD

• Nagaoka, Kanako, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Kanako Nagaoka, MD

• Fujiki, Tamami, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Tamami Fujiki, MD

• Kikuchi, Hiroaki, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Hiroaki Kikuchi, MD, PhD

• Mandai, Shintaro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Shintaro Mandai, MD, PhD, FASN

• Mori, Yutaro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Yutaro Mori, MD, PhD, FASN

• Mori, Takayasu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Takayasu Mori, MD, PhD

• Susa, Koichiro, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Koichiro Susa, MD, PhD

• Sohara, Eisei, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Eisei Sohara, MD, PhD

• Uchida, Shinichi, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Shinichi Uchida, MD, PhD

Background

Lipopolysaccharide-responsive beige-like anchor protein (LRBA) is essential for aquaporin-2 (AQP2) phosphorylation, and its absence results in the polyuric phenotype in mice. Most of the biallelic pathogenic mutations in the LRBA gene cause instability of the protein, resulting in LRBA deficiency. LRBA deficiency is a rare disease characterized by immune dysregulation and chronic diarrhea; however, the polyuric phenotype of LRBA deficiency has not been reported.

Methods

We established an international observational registry including 38 patients with LRBA deficiency. The physiological role of LRBA in sodium homeostasis was examined using Lrba^-/- mice.

Results

The urine specific gravity of LRBA deficiency patients (median, 1.008, n=17) was similar to Lrba ^-/- mice, and urine was dilute in spite of diarrhea-induced dehydration. Low urinary concentrating ability usually induces hypernatremia due to free-water diuresis. However, the serum sodium level of LRBA deficiency patients was low (median, 135 mEq/L, n=38). Therefore, we next investigated renal sodium homeostasis using Lrba knockout mice. Low-sodium diet (LSD) decreased serum sodium and chloride concentration in Lrba ^-/- mice (WT vs. Lrba ^-/-: Na 146.5 vs. 143.6 mEq/L, Cl 110.1 vs. 105.9 mEq/L). Thiazide diuretics which are inhibitors of sodium-chloride cotransporter (NCC) did not increase FENa in Lrba ^-/- mice fed with LSD. Due to the impairment of NCC activity, blood pressure was low in Lrba ^-/- mice and unresponsive to thiazide treatment. WNK-SPAK-NCC signaling is a main trigger to promote sodium reabsorption from urine via NCC. LRBA was colocalized with SPAK at intercellular vesicles in the distal convoluted tubules. In Lrba ^-/- mice, the protein expression level of SPAK was decreased and that of WNK was compensatorily increased. LRBA directly bound to SPAK and inhibited its lysosomal degradation.

Conclusion

We demonstrated that LRBA is essential for the activation of both NCC and AQP2, thereby ensuring sodium and water homeostasis in renal tubules. LRBA deficiency causes a loss of sodium and water into the urine, as well as diarrhea, which may be a strong risk factor for prerenal kidney failure due to dehydration. Careful attention to the sodium and water balance in patients with LRBA deficiency is required to prevent severe dehydration.

Funding

• Government Support – Non-U.S.