Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease.
BACKGROUND
Oxidative stress and inflammation are constant features and major mediators of progression and cardiovascular complications of chronic kidney disease (CKD). Hydrogen sulfide (H(2)S) is an endogenous signaling gas, which possesses potent anti-oxidant, anti-inflammatory, anti-hypertensive and other regulatory functions. H(2)S is produced by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MST). Plasma H(2)S is reduced in humans with hypertension, atherosclerosis and end-stage renal disease (ESRD). Atherosclerosis, hypertension and ischemia/reperfusion-induced acute kidney injury are associated with and, in part, mediated by diminished tissue H(2)S in experimental animals. Expression of the H(2)S-producing enzymes is reduced in the circulating leukocytes of patients with ESRD. However, the effect of CKD on expression of H(2)S-producing enzymes in the diseased kidney and other tissues is unknown and was studied here.


METHODS
Subgroups of rats were subjected to 5/6 nephrectomy or sham operation and observed for 6-12 weeks. Expression of H(2)S-producing enzymes and H(2)S-producing capacity was measured in kidney, liver and brain tissues.


RESULTS
The CKD group exhibited oxidative stress and significant reduction of plasma H(2)S concentration. This was associated with marked reduction of H(2)S-producing capacity of the kidney and liver, marked downregulation of CBS, CSE and MST in the kidney and of CBS and CSE expression in the liver. However, expression of H(2)S-producing enzymes in the brain was not significantly altered in CKD rats.


CONCLUSIONS
CKD is associated with significant reduction in plasma H(2)S concentration, diminished remnant kidney and liver tissue H(2)S-producing capacity and downregulation of the H(2)S-producing enzymes. Given the potent anti-oxidant, anti-inflammatory and cytoprotective properties of H(2)S, its deficiency may contribute to progression of CKD and the associated complications.
Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, CA, USA.
Mohammad A
MA
Aminzadeh
Nosratola D
ND
Vaziri
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001795:Blood Pressure Determination; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D006862:Hydrogen Sulfide / Q000032:analysis / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism; D009392:Nephrectomy; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D013858:Thiobarbiturates / Q000032:analysis / Q000378:metabolism*
D015415:Biomarkers; D017382:Reactive Oxygen Species; D013858:Thiobarbiturates; D008315:Malondialdehyde; C029684:thiobarbituric acid; D006862:Hydrogen Sulfide