Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease

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Abstract

Background.

Oxidative stress and inflammation are constant features and major mediators of progression and cardiovascular complications of chronic kidney disease (CKD). Hydrogen sulfide (H2S) is an endogenous signaling gas, which possesses potent anti-oxidant, anti-inflammatory, anti-hypertensive and other regulatory functions. H2S is produced by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MST). Plasma H2S 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 H2S in experimental animals. Expression of the H2S-producing enzymes is reduced in the circulating leukocytes of patients with ESRD. However, the effect of CKD on expression of H2S-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 H2S-producing enzymes and H2S-producing capacity was measured in kidney, liver and brain tissues.

Results.

The CKD group exhibited oxidative stress and significant reduction of plasma H2S concentration. This was associated with marked reduction of H2S-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 H2S-producing enzymes in the brain was not significantly altered in CKD rats.

Conclusions.

CKD is associated with significant reduction in plasma H2S concentration, diminished remnant kidney and liver tissue H2S-producing capacity and downregulation of the H2S-producing enzymes. Given the potent anti-oxidant, anti-inflammatory and cytoprotective properties of H2S, its deficiency may contribute to progression of CKD and the associated complications.

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