CHRONIC-RENAL-FAILURE INCREASES CYTOSOLIC CA2+ OF HEPATOCYTES

Chronic renal failure (CRF) is associated with increased Ca2+ content of liver and reduced hepatic lipase activity. This has been attributed to a rise in cytosolic Ca2+ ([Ca2+](i)) of the hepatocytes, but data on this issue are lacking. We examined the [Ca2+](i) and ATP content of hepatocytes as well as the activity of Na+-K+-adenosinetriphosphatase (Na+-K+-ATPase), Ca2+-ATPase, and Na+/Ca2(+) exchanger of hepatic membrane vesicles from normal rats, animals with 6 wk of CRF, CRF normocalcemic parathyroidectomized (CRF-PTX) rats, and CRF and normal animals treated with verapamil (CRF-V, normal-V). [Ca2+](i) in hepatocytes of CRF rats was higher (281 +/- 7.4 nM) and ATP lower (6.4 +/- 1.8 nmol/mg protein) than in normal (209 +/- 5.3 nM; 12.5 +/- 0.89 nmol/mg protein), CRF-PTX (212 +/- 1.0 nM; 13.7 +/- 0.79 nmol/mg protein), normal-V (215 +/- 2.3 nM; 14.2 +/- 0.77 nmol/mg protein), and CRF-V rats (209 +/- 7.4 nM; 14.8 +/- 0.72 nmol/10(6) cells). The Na+-K+-ATPase, the maximal velocity of Ca2+-ATPase, and the activity of the Na+/Ca2(+) exchanger were reduced, whereas the Michaelis constant of Ca2+-ATPase was increased in CRF rats compared with the other four groups of rats. The values in the latter groups were not different. These results indicate that 1) in CRF, the hepatocytes are overloaded with Ca2+, 2) this is due to excess parathyroid hormone (PTH) of CRF, since CRF-PTX rats had normal levels of [Ca2+](i), and 3) the increase in [Ca2+](i) is due to two processes: PTH-induced increased entry into hepatocytes, since treatment of CRF rats with verapamil, which blocks the action of PTH, prevented the rise in [Ca2+](i), and decreased Ca2+ extrusion out of these cells, attributable to impaired activities of Ca2+-ATPase, Na+-K+-ATPase, and Na+/Ca2+ exchanger.