Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filterability and implications for microangiopathy.
We have found a defect in the ouabain-sensitive Na+, K+-ATPase (Na+ pump, EC 3.6.1.37) of erythrocytes from streptozocin diabetic rats. This defect was accompanied by an increase in cell volume and osmotic fragility and a decrease in the cytosolic K+/Na+ ratio. There was also a doubling in the time needed for diabetic erythrocytes to pass through 4.7-micron channels in a polycarbonate filter. Our data are consistent with a primary defect in the erythrocyte Na+ pump and secondary changes in cell volume, osmotic fragility, K+/Na+ ratio, and cell filterability. All were reversed or prevented in vivo by insulin or the aldose reductase inhibitor Sorbinil. Protein kinase C agonists (phorbol ester and diacylglycerol) and agonist precursor (myoinositol) reversed the Na+ pump lesion, suggesting that protein kinase C-dependent phosphorylation of the 100-kDa subunit regulates Na+ pump activity and that insulin can influence erythrocyte protein kinase C activity. Ouabain inhibition of the erythrocyte Na+ pump also produced increases in cell size and reductions in rates of filtration. Theoretical treatment of the volume changes also predicts reduction in filterability as a consequence of cell swelling. We suggest that enlarged erythrocytes could play a role in the evolution of the microvascular changes of diabetes mellitus.
Kowluru
R
R
Life Sciences, Division, Los Alamos National Laboratory, NM 87545.
Bitensky
M W
MW
Kowluru
A
A
Dembo
M
M
Keaton
P A
PA
Buican
T
T
D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000097:blood*; D004907:Erythrocyte Deformability; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000502:physiology*; D006400:Hematocrit; D007093:Imidazoles / Q000627:therapeutic use; D048289:Imidazolidines; D007328:Insulin / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D009996:Osmotic Fragility; D010042:Ouabain / Q000494:pharmacology; D010766:Phosphorylation; D011188:Potassium / Q000097:blood; D011493:Protein Kinase C / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000097:blood; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000097:blood; D013012:Sorbitol / Q000097:blood
D007093:Imidazoles; D048289:Imidazolidines; D007328:Insulin; D015222:Sodium Channels; D013012:Sorbitol; D010042:Ouabain; D000255:Adenosine Triphosphate; D012964:Sodium; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil; D011188:Potassium