Kidney Week

Abstract: TH-PO202

SGLT2 Knockout Suppressed High Salt-Induced Organ Damage in Dahl Salt-Sensitive Rats

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Ito, Hiroki, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Hiroki Ito, MD

• Hirose, Takuo, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Takuo Hirose, PhD

• Sato, Shigemitsu, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Shigemitsu Sato, PhD

• Takahashi, Chika, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Chika Takahashi

• Ishikawa, Risa, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Risa Ishikawa, MD

• Endo, Akari, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Akari Endo, MD, PhD

• Yabana, Ikuko, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Ikuko Yabana, MD, PhD

• Mori, Takefumi, Tohoku Ika Yakka Daigaku, Sendai, Miyagi, Japan

Takefumi Mori, MD, PhD

Background

SGLT2 (sodium-glucose cotransporter 2) inhibitors have renoprotective properties through multiple mechanisms. DahlS (Dahl salt-sensitive) rats develop renal congestion and damage as a consequence of salt-sensitive hypertension. We aimed to investigate the effects of SGLT2 deficiency on the development of hypertension and renal injury in the DahlS rats fed a high-salt diet.

Methods

The Sglt2 gene was knocked out in DahlS rats (DahlS/mcwi) using the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9) system. DahlS-Sglt2^+/+ and DahlS-Sglt2^-/- male rats (8 weeks old) were fed normal salt (0.6% NaCl) or high salt (4% NaCl) diets for 2 weeks. The kidneys and hearts were harvested and analyzed by molecular and histological techniques.

Results

Elevated blood pressure by the tail-cuff method was observed in both DahlS-Sglt2^+/+ and DahlS-Sglt2^-/- rats following high-salt intake, with no significant difference between the two groups. Kidney and heart weights were significantly increased by the high-salt diet in DahlS-Sglt2^+/+ rats, while no changes were observed in DahlS-Sglt2^-/- rats. The expression of tubulointerstitial damage markers; Havcr1 (Kim1) and Spp1 (Opn) and interstitial fibrosis markers; Fn1, Vim, and Acta2 (α-Sma) was elevated in DahlS-Sglt2^+/+ rats fed a high-salt diet when compared with DahlS-Sglt2^+/+ rats fed a normal-salt diet. In contrast, no significant change was observed in the expression of these markers between the normal-salt and high-salt diets in DahlS-Sglt2^-/- rats. The levels of these markers in Dahl-Sglt2^-/- rats were significantly lower than those of Dahl-Sglt2^+/+ fed a high salt diet. The histological analysis also confirmed the results of the molecular analysis in both DahlS-Sglt2^+/+ and DahlS-Sglt2^-/- rats.

Conclusion

Our findings implicate that SGLT2 may play a protective role in the development of renal injury and fibrosis, independent of the increase in aortic blood pressure caused by salt-sensitive hypertension.