We previously demonstrated that aryl hydrocarbon receptor (AhR) activation attenuates the cytoprotective effect of hydrogen sulfide (H2S), leading to indoxyl sulfate (IS)-mediated renal tubular damage. However, it is unclear whether this pathway would be present in an in vivo uremic model.
Results:
In a rat chronic kidney disease (CKD) model with 5/6 nephrectomized (Nx), we found that poor renal filtration is associated with accumulation of IS and homocysteine (Hcy), an H2S precursor. Compared with controls, the protein and mRNA levels of H2S-producing enzymes, including cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, were attenuated in Nx kidneys. Since the transcription factor, specificity protein 1 (Sp1), acts as an upstream regulator of these enzyme expressions, we found that the protein level and activity of Sp1 were significantly decreased in Nx kidneys. Interestingly, employing the blocker of the AhR CH-223191 not only reverses the decrease in H2S-producing enzymes and Sp1, but it also reverses H2S reduction in Nx rats. These are associated with the mitigation of plasma Hcy accumulation, renal excretion, perfusion insufficiency, and tubular damage. Moreover, the oxidative stress in Nx kidneys due to increased superoxide formation and decreased glutathione contents was also attenuated by AhR inhibition.
Innovation:
Our findings highlight the deleterious effect of AhR activation on renal H2S formation may be due to IS accumulation and underline AhR blockade as a novel therapy for CKD.
Conclusion:
AhR is detrimental to Sp1 function in vivo, leading to impeding renal H2S generation and exacerbating oxidative stress during CKD progression. Antioxid. Redox Signal. 43, 448–464.
Get full access to this article
View all access options for this article.
References
1.
AminzadehMA, VaziriND. Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease. Nephrol Dial Transplant, 2012; 27(2):498–504; doi: 10.1093/ndt/gfr560
2.
AskariH, SeifiB, KadkhodaeeM, et al.Protective effects of hydrogen sulfide on chronic kidney disease by reducing oxidative stress, inflammation and apoptosis. Excli J, 2018; 17:14–23; doi: 10.1717/9/excli2017-711
3.
BosEM, LeuveninkHG, SnijderPM, et al.Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol, 2009; 20(9):1901–1905; doi: 10.1681/asn.2008121269
4.
ChangL, GengB, YuF, et al.Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids, 2008; 34(4):573–585; doi: 10.1007/s00726-007-0011-8
5.
DeguchiT, KusuharaH, TakadateA, et al.Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int, 2004; 65(1):162–174; doi: 10.1111/j.1523-1755.2004.00354.x
6.
DouL, PoitevinS, SalléeM, et al.Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int, 2018; 93(4):986–999; doi: 10.1016/j.kint.2017.11.010
7.
FengJ, LuX, LiH, et al.The roles of hydrogen sulfide in renal physiology and disease states. Ren Fail, 2022; 44(1):1289–1308; doi: 10.1080/0886022x.2022.2107936
8.
FuM, ZhangW, WuL, et al.Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc Natl Acad Sci U S A, 2012; 109(8):2943–2948; doi: 10.1073/pnas.1115634109
9.
GeY, JensenTL, MatherlyLH, et al.Synergistic regulation of human cystathionine-beta-synthase-1b promoter by transcription factors NF-YA isoforms and Sp1. Biochim Biophys Acta, 2002; 1579(2–3):73–80; doi: 10.1016/s0167-4781(02)00509-2
10.
GeY, MatherlyLH, TaubJW. Transcriptional regulation of cell-specific expression of the human cystathionine beta -synthase gene by differential binding of Sp1/Sp3 to the -1b promoter. J Biol Chem, 2001; 276(47):43570–43579; doi: 10.1074/jbc.M104930200
11.
GrishanovaAY, PerepechaevaML. Aryl Hydrocarbon Receptor in Oxidative Stress as a Double Agent and Its Biological and Therapeutic Significance. IJMS, 2022; 23(12):6719; doi: 10.3390/ijms23126719
12.
GyurászováM, GureckáR, BábíčkováJ, et al.Oxidative stress in the pathophysiology of kidney disease: Implications for noninvasive monitoring and identification of biomarkers. Oxid Med Cell Longev, 2020; 2020:5478708; doi: 10.1155/2020/5478708
13.
HanSJ, KimJI, ParkJW, et al.Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury. Nephrol Dial Transplant, 2015; 30(9):1497–1506; doi: 10.1093/ndt/gfv226
14.
IchiiO, Otsuka-KanazawaS, NakamuraT, et al.Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One, 2014; 9(9):e108448; doi: 10.1371/journal.pone.0108448
15.
KaplanP, TatarkovaZ, SivonovaMK, et al.Homocysteine and mitochondria in cardiovascular and cerebrovascular systems. Int J Mol Sci, 2020; 21(20):7698; doi: 10.3390/ijms21207698
16.
KimuraY, GotoY, KimuraH. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal, 2010; 12(1):1–13; doi: 10.1089/ars.2008.2282
17.
KobayashiA, SogawaK, Fujii-KuriyamaY. Cooperative interaction between AhR.Arnt and Sp1 for the drug-inducible expression of CYP1A1 gene. J Biol Chem, 1996; 271(21):12310–12316; doi: 10.1074/jbc.271.21.12310
18.
KoningAM, FrenayA-RS, LeuveninkHGD, et al.Hydrogen sulfide in renal physiology, disease and transplantation—The smell of renal protection. Nitric Oxide, 2015; 46:37–49; doi: 10.1016/j.niox.2015.01.005
19.
KuksisM, SmithPM, FergusonAV. Hydrogen sulfide regulates cardiovascular function by influencing the excitability of subfornical organ neurons. PLoS One, 2014; 9(8):e105772; doi: 10.1371/journal.pone.0105772
20.
LinCS, LeeSH, HuangHS, et al.H2O2 generated by NADPH oxidase 4 contributes to transient receptor potential vanilloid 1 channel-mediated mechanosensation in the rat kidney. Am J Physiol Renal Physiol, 2015; 309(4):F369–F376; doi: 10.1152/ajprenal.00462.2014
LiuF, YuanL, LiL, et al.S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis. Pharmacol Res, 2023; 192:106788; doi: 10.1016/j.phrs.2023.106788
LuCL, TengTY, LiaoMT, et al.TRPV1 hyperfunction contributes to renal inflammation in oxalate nephropathy. Int J Mol Sci, 2021a;22(12):6204; doi: 10.3390/ijms22126204
27.
LuCL, ZhengCM, LuKC, et al.Indoxyl-sulfate-induced redox imbalance in chronic kidney disease. Antioxidants (Basel), 2021b;10(6):936; doi: 10.3390/antiox10060936
28.
MacleanKN, KrausE, KrausJP. The dominant role of Sp1 in regulating the cystathionine beta-synthase-1a and -1b promoters facilitates potential tissue-specific regulation by Kruppel-like factors. J Biol Chem, 2004; 279(10):8558–8566; doi: 10.1074/jbc.M310211200
29.
MallamaciF, ZoccaliC, TripepiG, et al.; CREED Investigators. Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients. Kidney Int, 2002; 61(2):609–614; doi: 10.1046/j.1523-1755.2002.00144.x
30.
MannaP, JainSK. Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes. Journal of Biological Chemistry, 2012; 287(50):42324–42332; doi: 10.1074/jbc.M112.407833
31.
McFarlaneL, NelsonP, DugbarteyGJ, et al.Pre-treatment of transplant donors with hydrogen sulfide to protect against warm and cold ischemia-reperfusion injury in kidney and other transplantable solid organs. Int J Mol Sci, 2023; 24(4):3518; doi: 10.3390/ijms24043518
32.
MiaoH, CaoG, WuXQ, et al.Identification of endogenous 1-aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation. Br J Pharmacol, 2020; 177(15):3415–3435; doi: 10.1111/bph.15062
33.
NandiSS, MishraPK. H(2)S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes. Sci Rep, 2017; 7(1):3639; doi: 10.1038/s41598-017-03776-9
34.
NguyenC, EdgleyAJ, KellyDJ, et al.Aryl hydrocarbon receptor inhibition restores indoxyl sulfate-mediated endothelial dysfunction in rat aortic rings. Toxins (Basel), 2022; 14(2):100; doi: 10.3390/toxins14020100
35.
Perez-RuizL, Ros-LopezS, CardúsA, et al.A forgotten method to induce experimental chronic renal failure in the rat by ligation of the renal parenchyma. Nephron Exp Nephrol, 2006; 103(3):e126–e130; doi: 10.1159/000092198
36.
PernaAF, LucianoMG, IngrossoD, et al.Hydrogen sulphide-generating pathways in haemodialysis patients: A study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes. Nephrol Dial Transplant, 2009; 24(12):3756–3763; doi: 10.1093/ndt/gfp378
37.
PernaAF, SepeI, LanzaD, et al.Hydrogen sulfide increases after a single hemodialysis session. Kidney Int, 2011; 80(10):1108–1109; doi: 10.1038/ki.2011.285
38.
RyuH, LeeJ, ZamanK, et al.Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J Neurosci, 2003; 23(9):3597–3606; doi: 10.1523/jneurosci.23-09-03597.2003
39.
SahebnasaghA, HashemiJ, KhoshiA, et al.Aromatic hydrocarbon receptors in mitochondrial biogenesis and function. Mitochondrion, 2021; 61:85–101. ; doi: 10.1016/j.mito.2021.09.012
40.
ScammahornJJ, NguyenITN, BosEM, et al.Fighting oxidative stress with sulfur: Hydrogen sulfide in the renal and cardiovascular systems. Antioxidants (Basel), 2021; 10(3):373; doi: 10.3390/antiox10030373
41.
SchroederJC, DinataleBC, MurrayIA, et al.The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry, 2010; 49(2):393–400; doi: 10.1021/bi901786x
42.
SenU, MishraPK, TyagiN, et al.Homocysteine to hydrogen sulfide or hypertension. Cell Biochem Biophys, 2010; 57(2–3):49–58; doi: 10.1007/s12013-010-9079-y
43.
SongK, WangF, LiQ, et al.Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int, 2014; 85(6):1318–1329; doi: 10.1038/ki.2013.449
44.
StanfordEA, Ramirez-CardenasA, WangZ, et al.Role for the aryl hydrocarbon receptor and diverse ligands in oral squamous cell carcinoma migration and tumorigenesis. Mol Cancer Res, 2016; 14(8):696–706; doi: 10.1158/1541-7786.MCR-16-0069
45.
TsengYS, LiaoCH, WuWB, et al.N-methyl-D-aspartate receptor hyperfunction contributes to D-serine-mediated renal insufficiency. Am J Physiol Renal Physiol, 2021; 320(5):F799–F813; doi: 10.1152/ajprenal.00461.2020
46.
TsengYS, WuWB, ChenY, et al.Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys. Clin Sci (Lond), 2020; 134(19):2565–2580; doi: 10.1042/cs20200973
47.
UedaH, ShibaharaN, TakagiS, et al.AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases. Ther Apher Dial, 2007; 11(3):189–195; doi: 10.1111/j.1744-9987.2007.00430.x
48.
VeldmanBA, VervoortG, BlomH, et al.Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearance. Diabet Med, 2005; 22(3):301–305; doi: 10.1111/j.1464-5491.2005.01415.x
49.
Vodošek HojsN, BevcS, EkartR, et al.Oxidative stress markers in chronic kidney disease with emphasis on diabetic nephropathy. Antioxidants (Basel), 2020; 9(10):925; doi: 10.3390/antiox9100925
50.
WangW, HaoG, PanY, et al.Serum indoxyl sulfate is associated with mortality in hospital-acquired acute kidney injury: A prospective cohort study. BMC Nephrol, 2019; 20(1):57; doi: 10.1186/s12882-019-1238-9
51.
WeberGJ, PushpakumarS, TyagiSC, et al.Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension. Pharmacol Res, 2016; 113(Pt A):300–312; doi: 10.1016/j.phrs.2016.09.002
52.
WhitemanM, ArmstrongJS, ChuSH, et al.The novel neuromodulator hydrogen sulfide: An endogenous peroxynitrite ‘scavenger’? J Neurochem, 2004; 90(3):765–768; doi: 10.1111/j.1471-4159.2004.02617.x
53.
WollesenF, BrattströmL, RefsumH, et al.Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int, 1999; 55(3):1028–1035; doi: 10.1046/j.1523-1755.1999.0550031028.x.
54.
WuN, SiowYL, OK. Ischemia/reperfusion reduces transcription factor Sp1-mediated cystathionine beta-synthase expression in the kidney. J Biol Chem, 2010; 285(24):18225–18233; doi: 10.1074/jbc.M110.132142
55.
XieH, YangN, LuL, et al.Uremic toxin receptor AhR facilitates renal senescence and fibrosis via suppressing mitochondrial biogenesis. Adv Sci (Weinh), 2024; 11(33):e2402066; doi: 10.1002/advs.202402066
56.
XuZ, PrathapasingheG, WuN, et al.Ischemia-reperfusion reduces cystathionine-beta-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol, 2009; 297(1):F27–F35; doi: 10.1152/ajprenal.00096.2009
57.
YangQ, HeGW. Imbalance of homocysteine and H2S: Significance, mechanisms, and therapeutic promise in vascular injury. Oxid Med Cell Longev, 2019; 2019:7629673; doi: 10.1155/2019/7629673
58.
YangC-E, WangY-N, HuaM-R, et al.Aryl hydrocarbon receptor: From pathogenesis to therapeutic targets in aging-related tissue fibrosis. Ageing Research Reviews, 2022; 79:101662; doi: 10.1016/j.arr.2022.101662
59.
YangG, WuL, JiangB, et al.H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine gamma-lyase. Science, 2008; 322(5901):587–590; doi: 10.1126/science.1162667
60.
YeW, ChenR, ChenX, et al.AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1. Febs J, 2019; 286(21):4215–4231; doi: 10.1111/febs.14956
61.
YuM, KimYJ, KangDH. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol, 2011; 6(1):30–39; doi: 10.2215/cjn.05340610
62.
YuanX, LiD, ChenX, et al.Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis. Cell Death Dis, 2017a;8(12):3200; doi: 10.1038/s41419-017-0041-4
63.
YuanX, ZhangJ, XieF, et al.Loss of the protein cystathionine β-synthase during kidney injury promotes renal tubulointerstitial fibrosis. Kidney Blood Press Res, 2017b;42(3):428–443; doi: 10.1159/000479295
64.
ZhangDD, HanninkM. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol, 2003; 23(22):8137–8151; doi: 10.1128/mcb.23.22.8137-8151.2003
65.
ZhangQ, HuY, HuJE, et al.Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis. Life Sci, 2021; 278:119529; doi: 10.1016/j.lfs.2021.119529
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
