Uremic Toxin Indoxyl Sulfate Impairs Hydrogen Sulfide Formation in Renal Tubular Cells.

Chien-Lin Lu,Wen-Bin Wu,Kuo-Cheng Lu,Ming-Chieh Ma,Cai-Mei Zheng,Chun-Hou Liao

doi:10.3390/antiox11020361

Abstract

Hydrogen sulfide (H2S) was the third gasotransmitter to be recognized as a cytoprotectant. A recent study demonstrated that exogenous supplementation of H2S ameliorates functional insufficiency in chronic kidney disease (CKD). However, how the H2S system is impaired by CKD has not been elucidated. The uremic toxin indoxyl sulfate (IS) is known to accumulate in CKD patients and harm the renal tubular cells. This study therefore treated the proximal tubular cells, LLC-PK1, with IS to see how IS affects H2S formation. Our results showed that H2S release from LLC-PK1 cells was markedly attenuated by IS when compared with control cells. The H2S donors NaHS and GYY-4137 significantly attenuated IS-induced tubular damage, indicating that IS impairs H2S formation. Interestingly, IS downregulated the H2S-producing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), and these effects could be reversed by inhibition of the IS receptor, aryl hydrocarbon receptor (AhR). As transcription factor specificity protein 1 (Sp1) regulates the gene expression of H2S-producing enzymes, we further showed that IS significantly decreased the DNA binding activity of Sp1 but not its protein expression. Blockade of AhR reversed low Sp1 activity caused by IS. Moreover, exogenous H2S supplementation attenuated IS-mediated superoxide formation and depletion of the cellular glutathione content. These results clearly indicate that IS activates AhR, which then attenuates Sp1 function through the regulation of H2S-producing enzyme expression. The attenuation of H2S formation contributes to the low antioxidant defense of glutathione in uremic toxin-mediated oxidative stress, causing tubular cell damage.

Highlights

Hydrogen sulfide (H2 S) is a gaseous intracellular signaling transmitter, like nitric oxide and carbon monoxide
As the present results show that oxidative stress is associated with indoxyl sulfate (IS)/aryl hydrocarbon receptor (AhR)-mediated tubular damage by impeding H2 S formation, a detailed study is required to see whether this is dependent on the increased oxidation of 3-mercaptopyruvate sulfurtransferase (3-MST)
Our results show that treatment of the proximal tubule cells with IS impairs H2 S

Summary

Introduction

Hydrogen sulfide (H2 S) is a gaseous intracellular signaling transmitter, like nitric oxide and carbon monoxide. The half-life of H2 S in plasma is less than 30 min, and elimination occurs through excretion in exhaled breath [1] or through binding and oxidation by hemoglobin in the circulation (sulfhemoglobin) [2]. Antioxidants 2022, 11, 361 greater in lipophilic solvents than in water [3]. CBS and CSE are both dominant enzymes for renal H2 S generation that are mainly distributed in the proximal tubules and not in the glomerulus or the distal tubules [4]. Compared with CBS and CSE, 3-MST is broadly distributed in the kidneys, including in the proximal tubules, distal tubules, collecting duct, and renal pelvis [5].

Methods

Results

Discussion

Conclusion