Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.

Primary amyloidosis is a systemic disorder characterized by the clonal production and tissue deposition of immunoglobulin light chain (LC) proteins. Congestive heart failure remains the greatest cause of death in primary amyloidosis, due to the development of a rapidly progressive amyloid cardiomyopathy. Amyloid cardiomyopathy is largely unresponsive to current heart failure therapies, and is associated with a median survival of less than 6 months and a 5-year survival of less than 10%. The mechanisms underlying this disorder, however, remain unknown. In this report, we demonstrate that physiological levels of human amyloid LC proteins, isolated from patients with amyloid cardiomyopathy (cardiac-LC), specifically alter cellular redox state in isolated cardiomyocytes, marked by an increase in intracellular reactive oxygen species and upregulation of the redox-sensitive protein, heme oxygenase-1. In contrast, vehicle or control LC proteins isolated from patients without cardiac involvement did not alter cardiomyocyte redox status. Oxidant stress imposed by cardiac-LC proteins further resulted in direct impairment of cardiomyocyte contractility and relaxation, associated with alterations in intracellular calcium handling. Cardiomyocyte dysfunction induced by cardiac-LC proteins was independent of neurohormonal stimulants, vascular factors, or extracellular fibril deposition, and was prevented through treatment with a superoxide dismutase/catalase mimetic. This study suggests that cardiac dysfunction in amyloid cardiomyopathy is directly mediated by LC protein-induced cardiomyocyte oxidant stress and alterations in cellular redox status, independent of fibril deposition. Antioxidant therapies or treatment strategies aimed at eliminating circulating LC proteins may therefore be beneficial in the treatment of this fatal disease.

Renal tubular lesions induced by human Bence Jones protein in the rat: N-acetyl-beta-D-glucosaminidase as a sensitive marker.

The renal tubular lesion induced by human Bence Jones proteins (BJPs) in the rat was investigated to elucidate the initial role of BJPs in the genesis of renal tubular damage in myeloma kidney. Human BJP extracted from the urine collected from a patient with lambda light chain myeloma was given intraperitoneally to Sprague-Dawley rats with a daily dose of 300 mg/day for 5 days (BJP group, n = 16). Daily urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), which may represent the intensity of tubular damage, was measured. On days 10 and 20 after start of the injection, the kidneys were removed and examined by light and electron microscopy. The renal content of NAG was also measured to estimate the lysosomal activity. Both urinary and renal tissue NAG were significantly higher in the BJP group than in control rats injected with bovine serum albumin (n = 16). The most characteristic changes were found in the proximal tubules of the BJP group; the number and size of lysosomes were increased, and some showed enlargement with autophagic vacuolation. However, these were not found in the control group. There were no obvious changes in the distal tubules in either group, and the glomeruli appeared to be intact. These results suggest that BJP directly damages the proximal tubules via the process of catabolism, resulting in injury to these cells, and that the urinary NAG is a sensitive marker to detect early tubular damage by BJP.