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

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.