Inhibition of flippase-like activity by tubulin regulates phosphatidylserine exposure in erythrocytes from hypertensive and diabetic patients

Abstract

Plasma membrane tubulin is an endogenous regulator of P-ATPases and the unusual accumulation of tubulin in the erythrocyte membrane results in a partial inhibition of some their activities, causing hemorheological disorders like reduced cell deformability and osmotic resistance. These disorders are of particular interest in hypertension and diabetes, where the abnormal increase in membrane tubulin may be related to the disease development. Phosphatidylserine is more exposed on the membrane of diabetic erythrocytes than in healthy cells. In most cells, phosphatidylserine is transported from the exoplasmic to the cytoplasmic leaflet of the membrane by lipid flippases. Here we report that phosphatidylserine is more exposed in erythrocytes from both hypertensive and diabetic patients than in healthy erythrocytes, which could be attributed to the inhibition of flippase activity by tubulin. This is supported by: (i)- the translocation rate of a fluorescent phosphatidylserine analog in hypertensive and diabetic erythrocytes was slower than in healthy cells, (ii)- the pharmacological variation of membrane tubulin in erythrocytes and K562 cells was linked to changes in phosphatidylserine translocation, (iii)- the P-ATPase-dependent phosphatidylserine translocation in inside-out vesicles from human erythrocytes was inhibited by tubulin. These results suggest that tubulin regulates flippase activity and hence the membrane phospholipid asymmetry.

Lipidomics Profiling Reveals Serum Phospholipids Associated with Albuminuria in Early Type 2 Diabetic Kidney Disease

“…The lipids PS(27:0)-H and PS­(30:2e)-H both belong to phosphatidylserine (PS), which is the most abundant negatively charged glycerophospholipid in eukaryotic membranes. Physiologically, PS mostly exists in the interior of the plasma membrane and in a small amount in the exterior; it would be externalized to the extracellular surface during cell apoptosis induction under pathological factors such as infection, autoimmune attack, mitochondrial function, and so on. − It has been reported that PS is more exposed to red blood cells in hypertensive and diabetic patients than in healthy cohorts, which may be attributed to tubulin inhibition of flipping enzyme activity due to the possible inhibition of flippase activity by tubulin . Current studies reported that PS also externalizes to microparticles (MPs) in DKD, causing membrane remodeling.…”

“… 13 − 15 It has been reported that PS is more exposed to red blood cells in hypertensive and diabetic patients than in healthy cohorts, which may be attributed to tubulin inhibition of flipping enzyme activity due to the possible inhibition of flippase activity by tubulin. 16 Current studies reported that PS also externalizes to microparticles (MPs) in DKD, causing membrane remodeling. The most possible pathological mechanism is MPs formed under high glucose levels, inflammation, lipotoxicity, hypoxia, and uremic toxins.…”

Phosphatidylserine in Diabetes Research

“…Diabetes mellitus is associated with prothrombotic alterations . In diabetes, the abundance of PS on the membrane of diabetic erythrocytes and microparticles derived from blood cells is higher than that in healthy cells . In particular, meal intake increased PS-expressing platelet microparticles both in patients with T1D and T2D, with an accompanying increase in procoagulant potential .…”

“…54 In diabetes, the abundance of PS on the membrane of diabetic erythrocytes and microparticles derived from blood cells is higher than that in healthy cells. 55 In particular, meal intake increased PS-expressing platelet microparticles both in patients with T1D and T2D, with an accompanying increase in procoagulant potential. 56 However, another clinical experiment conducted with healthy individuals showed that erythrocytederived microparticles exhibit similar PS content and thrombin-related signaling after fasting and after two-meal intake.…”

Phospholipid scramblase 1: a protein with multiple functions via multiple molecular interactors

“…As expected, heightened expression of PLSCR1 and increased PS exposure were associated with increased fibrin turnover, which may explain, at least in part, the thrombophilia commonly reported in SLE patients [ 38 ]. An increase in PS scrambling to the outer membrane in erythrocytes has also been associated to other pathologies, such as diabetes and hypertension, which appears to be regulated by tubulin content and distribution and flippase activity [ 39 ]. Further studies should be conducted to elucidate the specific impact of PLSCR1 on this phenomenon.…”