Abstract Body: Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors confer cardiorenal protection through multifaceted mechanisms. Most of the current evidence is based on pharmacological studies using SGLT2 inhibitors, and research on the direct effects of SGLT2 gene deletion remain limited. This study aimed to elucidate the impact of Sglt2 gene deletion on high salt-induced organ damage and survival in Dahl salt-sensitive (DahlS) rats, a model susceptible to heart failure and renal injury under high-salt conditions.
Methods: The Sglt2 gene knocked out in DahlS rats (DahlS/MCWi) using the rGONAD method. At 8 weeks of age, male and female Sglt2^+/+ (WT) and Sglt2^-/- (KO) DahlS rats were fed either a normal-salt diet (0.6% NaCl) or a high-salt diet (4% NaCl) for 2 weeks. Systolic blood pressure was measured by the tail-cuff method. Cardiorenal damage was assessed by molecular and histological analyses. Survival analysis was performed under both dietary conditions, with endpoints defined as sudden death or euthanasia due to animal welfare concerns, including limb paralysis.
Results: High-salt loading significantly increased blood pressure in both genotypes, with no significant difference between WT and Sglt2 KO rats. The high salt-induced increase in the heart weight was attenuated in Sglt2 KO rats. Furthermore, Sglt2 KO rats showed reduced expression of renal injury and fibrosis markers under high-salt conditions. Histological analysis confirmed reduced cardiac and renal fibrosis in Sglt2 KO rats fed high-salt diet compared to WT rats fed high-salt diet. In the survival analysis, no rats in both genotypes reached an endpoint during the duration period of over 200 days under the normal-salt diet. In contrast, under high-salt diet, rats in both genotypes and sexes began reaching endpoints after approximately 30 days with no significant difference in survival duration between groups. The predominant cause of endpoint events under the high-salt diet was limb paralysis due to stroke.
Conclusion: Sglt2 deletion did not affect salt-sensitive blood pressure elevation but attenuated high salt-induced damage in the heart and kidneys. These findings suggest that the protective effects of SGLT2 inhibitors on the heart and kidneys may involve mechanisms independent of blood pressure. However, the absence of survival benefit in Sglt2 KO rats, where stroke was the primary cause of adverse outcomes, implies that SGLT2 inhibition might offer limited protection against stroke.