Sglt2 deletion attenuates cardiorenal damage but not stroke or mortality in Dahl salt-sensitive hypertensive rats

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 has been limited. Dahl salt-sensitive (DahlS) rats develop volume overload-induced heart failure and renal failure under high-salt conditions, with mechanisms of renal dysfunction reported to be predominantly renal congestion secondary to heart failure—representing cardiorenal syndrome—in addition to hypertensive renal injury. This study aimed to elucidate the impact of Sglt2 gene deletion on high salt-induced organ damage and survival in DahlS rats.

The Sglt2 gene was knocked out in DahlS rats (DahlS/MCWi) using the rGONAD (rat genome-editing via oviductal nucleic acids delivery) method. At 8 weeks of age, male Sglt2+/+ (wild type: WT) and Sglt2-/- (knockout: 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. In a separate long-term experiment, survival analysis was performed under both dietary conditions, with endpoints defined as sudden death or euthanasia due to animal welfare concerns (primarily hemiplegia).

High salt loading significantly increased blood pressure in both WT and KO groups, with no significant difference between genotypes. The high salt-induced increase in heart weight was attenuated in Sglt2 KO rats. Furthermore, Sglt2KO rats showed reduced expression of renal injury and fibrosis markers under high salt conditions. Histological analysis confirmed reduced cardiac and renal injury and 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 observation period of over 200 days under the normal salt diet. In contrast, under the 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 hemiplegia due to stroke.

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. Considering that previous studies have not demonstrated clear organ-protective effects with SGLT2 knockout alone, the unique pathophysiology of cardiorenal syndrome in DahlS rats may have contributed to the protective effects observed in this study. However, the absence of survival benefit in Sglt2 KO rats, where stroke was the primary cause of adverse outcomes, has important implications. This suggests that hypertension remains the dominant stroke risk factor, or that SGLT2 inhibition provides limited cerebrovascular protection.