Dapagliflozin Treatment Augments Bioactive Phosphatidylethanolamine Concentrations in Kidney Cortex Membrane Fractions of Hypertensive Diabetic db/db Mice and Alters the Density of Lipid Rafts in Mouse Proximal Tubule Cells

Abstract

In addition to inhibiting renal glucose reabsorption and allowing for glucose excretion, the sodium/glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin may be efficacious in treating various comorbidities associated with type 2 diabetes mellitus (T2DM). The molecular mechanisms by which dapagliflozin exerts its beneficial effects are largely unknown. We hypothesized dapagliflozin treatment in the diabetic kidney alters plasma membrane lipid composition, suppresses extracellular vesicle (EV) release from kidney cells, and disrupts lipid rafts in proximal tubule cells. In order to test this hypothesis, we treated diabetic db/db mice with dapagliflozin (N = 8) or vehicle (N = 8) and performed mass spectrometry-based lipidomics to investigate changes in the concentrations of membrane lipids in the kidney cortex. In addition, we isolated urinary EVs (uEVs) from urine samples collected during the active phase and the inactive phase of the mice and then probed for changes in membrane proteins enriched in the EVs. Multiple triacylglycerols (TAGs) were enriched in the kidney cortex membrane fractions of vehicle-treated diabetic db/db mice, while the levels of multiple phosphatidylethanolamines were significantly higher in similar mice treated with dapagliflozin. EV concentration and size were lesser in the urine samples collected during the inactive phase of dapagliflozin-treated diabetic mice. In cultured mouse proximal tubule cells treated with dapagliflozin, the lipid raft protein caveolin-1 shifted from less dense fractions to more dense sucrose density gradient fractions. Taken together, these results suggest dapagliflozin may regulate lipid-mediated signal transduction in the diabetic kidney.

The influence of dapagliflozin on cardiac remodeling, myocardial function and metabolomics in type 1 diabetes mellitus rats

“…Decreased phosphatidylethanolamine content was reported in heart membranes isolated from streptozotocin-induced diabetic rats in combination with sarcolemmal Ca 2+ transport changes [ 65 ]. In accordance with our study, dapagliflozin increased phosphatidylethanolamine concentration in renal cortex membrane of diabetic mice [ 66 ]. On the other hand, SGLT2 inhibition decreased myocardial ceramide levels in Type 2 DM rats [ 67 ].…”

Combined untargeted and targeted lipidomics approaches reveal potential biomarkers in type 2 diabetes mellitus cynomolgus monkeys

“…There are several strengths of this study. The cynomolgus monkey model of T2DM in the present study is a naturally occurring and clinically relevant experimental model that exhibits several characteristics frequently observed in diabetic patients including dyslipidemia 51,52 . Another strength is that, to our knowledge, this research was among the first to comparative analysis of fasting serum lipidomic profiles in T2DM cynomolgus monkeys combined untargeted and targeted lipidomics approaches.…”

“…The cynomolgus monkey model of T2DM in the present study is a naturally occurring and clinically relevant experimental model that exhibits several characteristics frequently observed in diabetic patients including dyslipidemia. 51,52 Another strength is that, to our knowledge, this research was among the first to comparative analysis of fasting serum lipidomic profiles in T2DM cynomolgus monkeys combined untargeted and targeted lipidomics approaches. Thus, the comparative analysis of serum lipidomics data to explore the associations between altered lipid profiles and the onset of T2DM not only provides insights into the pathophysiology of DM but also leads to the development of novel means of treating DM.…”

Molecular mechanism of renal lipid accumulation in diabetic kidney disease

“… 122 Interestingly, research also found that SGLT2 inhibitor dapagliflozin treatment in db/db diabetic mice altered the concentration of membranous lipids in the kidney cortex based on mass spectrometry lipidomics. 123 The role of SGLT2 inhibitors in renal lipid regulation in the context of DKD was also supported by human study. A moderate size of prospective study demonstrated that diabetic patients treated with metformin and empagliflozin had lower advanced glycation end products levels and renal fat accumulation than those treated only with metformin.…”