Increase in renal glutathione in cholestatic liver disease is due to a direct effect of bile acids

Abstract

Hepatic synthesis and plasma levels of glutathione are markedly decreased in chronic liver disease. Because glutathione turnover is highest in kidneys, we examined whether changes in kidney glutathione occur in chronic cholestasis and whether they are related to kidney dysfunction in liver disease. Kidney and plasma GSH and GSSG were measured 1) in bile duct-ligated (BDL) rats; 2) in healthy rats after bile acid loading to mimic cholestasis; and 3) after irreversible inhibition of glutathione synthetase with buthionine-sulfoximine (BSO), where glutathione consumption, urinary volume, and sodium excretion were also estimated. In addition, γ-glutamylcysteine synthetase (γ-GCS) mRNA, protein, and enzymatic specific activity were measured in kidney tissue after BDL. After BDL, kidney GSH and GSSG increased within hours by 67 and 66%, respectively. The increases were not related to plasma glutathione, which decreased below control values. Intravenous bile acid loading caused identical increases in GSH and GSSG as occurred after BDL, when glycine- or taurine-conjugated dihydroxy bile acids were administered. Glutathione consumption, as estimated after blocking of de novo synthesis with BSO, was significantly increased after BDL (127 vs. 44 nmol · g−1 · min−1). γ-GCS mRNA and enzymatic specific activity were significantly reduced 5 days after BDL, whereas protein concentrations did not change. The urinary sodium concentration was 70% lower in BDL than in control rats. Depletion of renal glutathione normalized sodium excretion by increasing urinary sodium concentration and urinary volume. The increase in kidney glutathione after BDL seems to be mediated by an increase in plasma bile acids and is critically related to sodium retention. The increase in GSH consumption despite reduced γ-GCS activity indicates a decreased GSH turnover tentatively due to reduced renal GSH efflux by competition with organic anions at membrane transport proteins.

HEPATIC AND EXTRAHEPATIC SYNTHESIS AND DISPOSITION OF DINITROPHENYL-S-GLUTATHIONE IN BILE DUCT-LIGATED RATS

“…Whereas liver and intestinal content of GSH were reduced in BDL rats (see Table 2), renal content was significantly increased at day 7 postsurgery, consistent with the induction of GSTs and maximum increase in urinary excretion of DNP-SG observed in vivo. Our data on increased renal content of GSH are in agreement with a previous study from Purucker et al (2002), who postulated that reduced renal efflux of GSH by competition with organic anions at the membrane transporter level leads to its decreased turnover and increased cellular accumulation. We postulate that this intracellular pool of GSH is critical for increased conversion of CDNB to DNP-SG for subsequent excretion into urine in rats with obstructive cholestasis.…”

Basal release of nitric oxide in the mesenteric artery in portal hypertension and cirrhosis: Role of dimethylarginine dimethylaminohydrolase

“…This higher expression could be related to the increase of plasmatic levels of bile acids in the BDE group. It has been described that in the BDE‐induced cirrhosis model, plasmatic bile acids are increased approximately 25‐fold compared with Sham‐operated controls . This increment is detected by the farnesoid X receptor, a bile acid‐responsive nuclear receptor, inducing a DDAH‐1 gene upregulation …”

“…It has been described that in the BDE-induced cirrhosis model, plasmatic bile acids are increased approximately 25-fold compared with Sham-operated controls. 29 This increment is detected by the farnesoid X receptor, a bile acid-responsive nuclear receptor, inducing a DDAH-1 gene upregulation. 30 That ADMA and L-NAME did not inhibit acetylcholineinduced relaxation in our study indicates that NO-independent pathways contribute to this effect.…”

Melatonin prevents increased asymmetric dimethylarginine in young rats with bile duct ligation

“…To restore a normal GSH/GSG ratio, excess GSSG is either exported from the cell or intracellular GSH increases. Cholestasis has a strong impact on renal GSH metabolism; kidney GSSG increases immediately, followed by a pronounced GSH increase and this persists up to 5–6 wk after BDL [34]. Thus, the kidney GSH/GSSG ratio is not different in adult BDL rats compared with shams [35].…”