Abstract 16016: A Soluble Inhibitor Depresses Na/K ATPase Activity in Cardiomyopathic Hearts from Uremic Rats
Chronic kidney disease is associated with a cardiomyopathy characterised by hypertrophy, hypertension, myocardial fibrosis, reduced cardiac output and increased arrhythmias. We have previously shown that myocytes isolated from uremic (5/6ths nephrectomized rats) show changes in EC coupling consistent with Na and Ca overload. We have therefore investigated the effects of uremia on Na/K ATPase, SERCA2a and their accessory proteins phospholemman (PLM) and phospholamban (PLB). Control rats underwent bilateral renal decapsulation, without removal of renal tissue while uremic animals were subjected to 5/6ths nephrectomy. Uremic animals showed progressive LV hypertrophy (increased heart dry wt to tibia length: 0.45±0.01 vs 0.38±0.01 g/cm, n=26; p<0.05 vs sham), elevated systolic (163±1 vs 147±2 mmHg, n=26; p<0.01 vs sham) and diastolic blood pressure (106±1 vs 95±1 mmHg, n=26; p<0.01 vs sham), as well as elevated serum urea concentration (15.5±0.4 vs 6.4±0.4mM, n=26; p<0.01 vs sham). There was an increased expression of both α1 (49±6%, n=8; p<0.05) and α2 (37±7%, n=8; p<0.05) Na/K ATPase subunits in uremic hearts cf sham. There was no change in total SERCA2a, PLM or PLB expression. However, there was a significant increase in phosphorylation of PLM Ser 68 and Thr 69 and PLB Ser 16 and Thr 17 residues in uremic animals, cf sham (n=8; p<0.05). Surprisingly, despite increased expression of Na/K ATPase catalytic subunit, and elevated PLM phosphorylation, Na/K ATPase activity in crude ventricular homogenates was decreased in uremic hearts (37±20 vs 66±13μmol/g/5min, n=8; p<0.05 vs sham). However, when sarcolemmal membranes were purified away from the soluble homogenate, Na/K ATPase activity in uremic hearts was stimulated compared to sham-operated animals (75±21 vs 29±8μmol/g/5min, n=8; p<0.05). This suggests the presence of an unidentified Na/K ATPase inhibitor in the crude ventricular homogenate that does not co-purify with sarcolemmal membranes. The changes in PLM phosphorylation and Na/K ATPase α subunit expression may reflect an adaptive change to the reduced pump function mediated by the presence of this inhibitor. These results are consistent with Na and Ca overload contributing to the contractile dysfunction observed in uremic cardiomyopathy.
- © 2010 by American Heart Association, Inc.