Kidney Week

Abstract: FR-PO287

Role of Glutamine Transporter Snat3 in Promoting Polycystic Kidney Disease

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Yamaguchi, Shinobu, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Shinobu Yamaguchi,

• Sedaka, Randee S., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Randee S. Sedaka,

• Shinde, Sejal Sanjay, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Sejal Sanjay Shinde,

• Huang, Jifeng, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Jifeng Huang,

• Hsu, Jung-Shan, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Jung-Shan Hsu,

• Saigusa, Takamitsu, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

Takamitsu Saigusa,

Background

Disease severity of polycystic kidney disease (PKD) is influenced by diet. High protein (HP) diet is one of the most recognized PKD progression-accelerating factors. Dietary protein is catabolized into amino acids (AA) and delivered to the kidney, activating the mTOR pathway and renal hypertrophy. Renal hypertrophic signaling superimposed in PKD mice increases immune cell response, inflammation and accelerates cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately activating the immune cell response and accelerating cyst growth.

Methods

Adult tamoxifen-inducible Pkd1^flox/flox mice with and without Cre (CAGG-ER2) were given tamoxifen to induce gene deletion. Two weeks later, mice were fed either a high (HP; 60%), normal (NP;18%) or low (LP; 6%) protein diet (all isocaloric 3.7kcal/g, restricted to 2.8g/day) for 1 week. Mice were then euthanized and tissues were used for histology, immunofluorescence (IF), RT-PCR and Western blot. Kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing.

Results

Pkd1 knockout (Pkd1KO) mice fed a HP diet for 1 week had increased kidney weight/body weight ratio and cystic area compared to NP or LP fed counterparts. However, there were no differences in the number of renal macrophages, pro-inflammatory cytokines, or markers of proximal tubular injury at this early stage. RNA sequencing of renal tubular epithelial cells from Pkd1KO mice fed a HP- compared to NP- or LP diet revealed increased gene expression of sodium-glutamine transporter Snat3 and gluconeogenesis marker Pepck1, confirmed by RT-PCR. Snat3 expression by IF along cyst-lining tubular epithelial cells, as well as pS6 protein abundance, increases in HP- compared to LP diet fed Pkd1KO mice. Urinary ammonia, a byproduct of glutamine, was elevated in Pkd1KO mice fed a HP- compared to NP- or LP diet.

Conclusion

One-week feeding with HP- compared to NP- or LP diet increased the expression of glutamine transporter Snat3, gluconeogenesis, mTOR and cyst growth prior to increases in macrophage number and cytokines in Pkd1KO mice. Glutamine in dietary protein may accelerate cyst growth through Snat3 during early stages of PKD.

Funding

• NIDDK Support