The relationship between sodium chloride concentration and bile acid cytotoxicity in culltured kidney cells

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Abstract
Patients with obstructive jaundice suffer an increased incidence of mortality from post operative renal failure, which may be related to elevated circulating bile salts. This study assesses the effects of increased ionic strength (similar to that found in the kidney inner medulla) on bile salt critical micellar concentration (CMC) and cytotoxicity to renal medullary epithelial primary cultures and MDCK and NRK cell lines representing the distal and proximal tubular cells respectively. The CMC of chenodeoxycholic acid decreased from 2.86 +/- 0.07 (in isotonic Earle's Hepes buffer) to 2.30 +/- 0.07, 1.99 +/- 0.09 and 1.46 +/- 0.08 mM following the addition of 150, 250 and 500 mM NaCl. Similarly, the CMC of deoxycholic acid was reduced from 3.18 +/- 0.1 to 2.84 +/- 0.1, 2.26 +/- 0.1 and 1.79 +/- 0.09 mM by the addition of 150, 250 and 500 mM NaCl. Increasing the ionic strength of the culture medium of medullary epithelial cells by the addition of 150 mM NaCl, decreased viability by 39% (p < 0.01), 24% (p < 0.001) and 40% (p < 0.001) for lithocholic (25 microM), chenodeoxycholic (100 microM) and deoxycholic acids (100 microM), respectively. A similar increase in the ionic strength of the culture medium of MDCK cells decreased viability by 79% (p < 0.01), 46% (p < 0.01) and 15% (p < 0.01) for lithocholic (15 microM), chenodeoxycholic (100 microM) and deoxycholic (50 microM), respectively. Adding 200 mM urea to medium supplemented with 150 mM NaCl (to further increase osmolality but not ionic strength) had no effect on the cytotoxicity bile salts in MDCK cells. The addition of 150 mM NaCl to the culture medium of NRK cells resulted in a decrease viability of 15% (p < 0.01), 27% (p < 0.01) and 60% (p < 0.01) following exposure to either lithocholic (15 microM), chenodeoxycholic (50 microM) or deoxycholic acids (50 microM) respectively. These results show that increasing NaCl concentrations lowers CMC of bile salts and increase cytotoxicity in medullary epithelial primary, MDCK and NRK cells. This suggests that the high NaCl levels in the kidney inner medulla would reduce bile salt CMC such that they could damaged renal cells. This may, in part, explain the increased susceptibility of the kidney during obstructive liver disease.