Effect of Chronic Renal Failure on Cardiac Contractile Function, Calcium Cycling, and Gene Expression of Proteins Important for Calcium Homeostasis in the Rat

Abstract

Abstract. Patients with chronic renal failure frequently develop cardiac hypertrophy and diastolic dysfunction; however, the mechanisms by which this occurs are still unclear. Male Sprague-Dawley rats were subjected to 5/6 nephrectomy and studied for their isolated myocyte function, calcium cycling, and gene expression of proteins important in calcium homeostasis after 4 wk. Comparable rats subjected to suprarenal aortic banding for the same duration were used for comparison. Rats subjected to 5/6 nephrectomy and aortic banding developed comparable hypertension; however, rats subjected to 5/6 nephrectomy experienced a greater degree of cardiac hypertrophy and downregulation of cardiac sodium potassium ATPase (Na ϩ /K ϩ -ATPase) activity than rats subjected to aortic banding. Moreover, cells isolated from the 5/6 nephrectomy rat hearts displayed impaired contractile function and altered calcium cycling compared with cells isolated from control or aortic constriction rat hearts. The 5/6 nephrectomy rat heart cells displayed a prolonged time constant for calcium recovery following stimulation, which corresponded to decreases in homogenate sarcoplasmic reticulum calcium ATPase-2a (SERCA2a) activity, protein density, and mRNA for SERCA2a. In conclusion, chronic renal failure leads to alterations in cardiac gene expression, which produces alterations in cardiac calcium cycling and contractile function. These changes cannot be explained only by the observed increases in BP. jshapiro@mco.eduPatients with renal failure usually develop cardiac complications. In end-stage renal disease (ESRD) patients treated with hemodialysis in the United States, annual mortality rates exceed 20%, with more than 50% attributed to cardiac mortality (1). Although the term "uremic cardiomyopathy" had previously been used to refer to a dilated cardiomyopathy complicating renal failure, more recent studies suggest that the most common form of heart disease in renal failure patients is one characterized by diastolic dysfunction and left ventricular hypertrophy (2). Although a number of known factors have been implicated in the pathogenesis of the left ventricular hypertrophy and diastolic dysfunction, our understanding of these processes is still incomplete (3).For many years, it has been known that the sodium pump is abnormal in chronic renal failure and that circulating inhibitor(s) can be demonstrated in the serum of uremic patients (4 -6). We have observed that sodium pump inhibition initiates a signal cascade that can cause alterations in gene transcription and ultimately produce hypertrophy in cardiomyocytes grown in culture (7-9). We have also observed that sodium pump inhibitors, including those circulating in the serum of uremic patients, can acutely cause altered calcium cycling and cardiomyocyte relaxation through sodium pump inhibition (10). The following studies were performed to further examine how cardiac growth and function are chronically modified by the uremic milieu. Materials and Methods AnimalsMale Sprague-Dawley rats (200...

Gene expression in uremic left ventricular hypertrophy: effects of hypertension and anemia

“…However, the mechanism which this occurs and the major players in the pathogenesis are still unclear. Our study demonstrated that treatments of arterial hypertension and anemia partially ameliorated but did not completely correct cardiac and left ventricular hypertrophy in uremic rats, which was in an agreement with the results presented by others (Rambausek et al, 1985;Kennedy et al, 2003).…”

“…Fast-migrating V1 isomyosin was increased in uremia. In end-stage-renal disease the elevated serum hepatocyte growth factor (Malatino et al, 2003) or calcium homeostasis (Kennedy et al, 2003) seemed to be associated with LVH. However, the mechanism which this occurs and the major players in the pathogenesis are still unclear.…”

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

“…In particular, we have previously used Indo-1 to study calcium transients with our system. 28,33,53 However, in these experiments in which we anticipated substantial increases in the pHi in the aldosteronetreated cells, we chose to use Fluo-3 because it is relatively pH-insensitive while still giving extremely high signal-tonoise ratio. Despite our stable time controls, it is possible that during the short-term experiments performed, some dye leakage occurred in the spironolactone group, and some increases in cytosolic calcium, especially systolic values, could have been missed.…”

Uremic Cardiomyopathy and Insulin Resistance

“…Uremia is associated with depressed cardiac function at the level of the myocyte, [123][124][125] independent of gross alterations in cardiac structure, or ␤-adrenoreceptor desensitization. 123,124 Although the underlying mechanism is not fully understood, two groups independently identified prolongation of the calcium transient, 123,125 without a change in amplitude or rate of sarcoplasmic reticulum calcium release.…”