Kidney Week

Abstract: TH-PO339

LRBA Is Essential for Urinary Concentration and Body Water Homeostasis

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

• 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic

Authors

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

Yu Hara,

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

Fumiaki Ando,

• Oikawa, Daisuke, Osaka Koritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka, Osaka, Osaka, Japan

Daisuke Oikawa,

• Ichimura, Koichiro, Juntendo Daigaku Igakubu Daigakuin Igaku Kenkyuka, Bunkyo-ku, Tokyo, Japan

Koichiro Ichimura,

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

Tamami Fujiki,

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

Shintaro Mandai,

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

Takayasu Mori,

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

Koichiro Susa,

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

Eisei Sohara,

• Rai, Tatemitsu, Tokyo Ika Shika Daigaku, Bunkyo-ku, Tokyo, Japan

Tatemitsu Rai,

• Tokunaga, Fuminori, Osaka Koritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka, Osaka, Osaka, Japan

Fuminori Tokunaga,

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

Shinichi Uchida,

Background

Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. Over 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration.

Methods

PKA activation by several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were well correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We generated Lrba knockout mice to examine pathophysiological roles of LRBA.

Results

LRBA colocalized with AQP2 at the same intracellular vesicles in the subapical region of renal collecting ducts. AQP2 phosphorylation at S256 and S269 via vasopressin / cAMP / PKA signaling was severely impaired in Lrba knockout mice, leading to the defective AQP2 trafficking to the apical plasma membrane. Lrba knockout mice showed water diuresis and subsequent compensatory increase in serum vasopressin levels. Urine osmolality did not elevate even by the administration of exogenous vasopressin. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts.

Conclusion

LRBA is the first PKA-anchoring protein discovered to be crucial for PKA-induced AQP2 phosphorylation and urinary concentration.

Funding

• Government Support – Non-U.S.