Underlying molecular mechanisms of the kidney protective effects of
sodium glucose co-transporter 2 (
SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary
epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with
type 2 diabetes (T2D). The underlying molecular mechanisms of the
SGLT2 inhibitor canagliflozin on
EGF using single-cell
RNA sequencing from kidney tissue were examined. Urinary
EGF-to-
creatinine ratio (uEGF/Cr) was measured in 3521
CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell
RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with
canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D,
EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased
EGF levels closer to the healthy state. In young persons with T2D without SGLT2i,
endothelin-1 emerged as a key regulator of the
EGF co-expression network. SGLT2i treatment was associated with a shift towards normal
EGF expression. Thus, decreased uEGF represents increased risk of
kidney disease progression in patients with T2D.
Canagliflozin increased kidney tissue expression of
EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.