Ischemia/Reperfusion Reduces Transcription Factor Sp1-mediated Cystathionine β-Synthase Expression in the Kidney

Cystathionine β-synthase (CBS) is a key enzyme that catalyzes the rate-limiting step for homocysteine (Hcy) metabolism via the trans-sulfuration pathway and is also responsible for the production of H2S through the desulfhydration reaction. Our recent studies demonstrate that renal ischemia/reperfusion decreased the CBS activity leading to Hcy accumulation and H2S reduction in the kidney, which in turn contributed to kidney injury. Both Hcy and H2S play important roles in physiological and pathological processes. In this study we investigated the molecular mechanism by which CBS activity was regulated in the kidney. The left kidney of Sprague-Dawley rat was subjected to 45 min of ischemia followed by 6 h of reperfusion. Ischemia/reperfusion caused a significant decrease in CBS mRNA and protein levels in the kidney. As a consequence, there was a marked reduction in the CBS enzyme activity. Transfection of kidney proximal tubular cells with transcription factor (Sp1) small interfering RNA caused a marked reduction in CBS mRNA, indicating a pivotal role for Sp1 in regulating CBS expression in kidney cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay detected a lower Sp1 activity in kidneys subjected to ischemia/reperfusion as compared with that in a sham-operated group. ERK-mediated phosphorylation of Sp1 was responsible for a decreased transcriptional activity of Sp1 in the kidney upon ischemia/reperfusion. These results suggest that reduced kidney CBS gene expression during ischemia/reperfusion is mediated via a decrease in Sp1 transcriptional activity. Regulation of CBS-mediated Hcy and H2S homeostasis may offer a renal protective effect against ischemia/reperfusion injury. Cystathionine β-synthase (CBS) is a key enzyme that catalyzes the rate-limiting step for homocysteine (Hcy) metabolism via the trans-sulfuration pathway and is also responsible for the production of H2S through the desulfhydration reaction. Our recent studies demonstrate that renal ischemia/reperfusion decreased the CBS activity leading to Hcy accumulation and H2S reduction in the kidney, which in turn contributed to kidney injury. Both Hcy and H2S play important roles in physiological and pathological processes. In this study we investigated the molecular mechanism by which CBS activity was regulated in the kidney. The left kidney of Sprague-Dawley rat was subjected to 45 min of ischemia followed by 6 h of reperfusion. Ischemia/reperfusion caused a significant decrease in CBS mRNA and protein levels in the kidney. As a consequence, there was a marked reduction in the CBS enzyme activity. Transfection of kidney proximal tubular cells with transcription factor (Sp1) small interfering RNA caused a marked reduction in CBS mRNA, indicating a pivotal role for Sp1 in regulating CBS expression in kidney cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay detected a lower Sp1 activity in kidneys subjected to ischemia/reperfusion as compared with that in a sham-operated group. ERK-mediated phosphorylation of Sp1 was responsible for a decreased transcriptional activity of Sp1 in the kidney upon ischemia/reperfusion. These results suggest that reduced kidney CBS gene expression during ischemia/reperfusion is mediated via a decrease in Sp1 transcriptional activity. Regulation of CBS-mediated Hcy and H2S homeostasis may offer a renal protective effect against ischemia/reperfusion injury. IntroductionHomocysteine (Hcy) 2The abbreviations used are: HcyhomocysteineCBScystathionine β-synthaseChIPchromatin immunoprecipitation assayEMSAelectrophoretic mobility shift assayGAPDHglyceraldehyde-3-phosphate dehydrogenasesiRNAsmall interfering RNAERKextracellular signal-regulated kinaseMAPmitogen-activated protein kinase. and H2S are two important molecules produced in the body during the metabolism of sulfur amino acids. Cystathionine β-synthase (CBS, EC 4.2.1.22) is a key enzyme that regulates the metabolism of Hcy and H2S (1Eto K. Kimura H. J. Biol. Chem. 2002; 277: 42680-42685Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Hcy is an intermediate amino acid formed during the conversion of methionine to cysteine and is central to the supply of methyl groups that are critical to normal cell function. Hcy can be metabolized via two major pathways, namely the remethylation pathway (remethylation of Hcy to methionine) and the trans-sulfuration pathway (trans-sulfuration of Hcy to cysteine) (2Wang L. Jhee K.H. Hua X. DiBello P.M. Jacobsen D.W. Kruger W.D. Circ. Res. 2004; 94: 1318-1324Crossref PubMed Scopus (82) Google Scholar). CBS catalyzes the rate-limiting step in the trans-sulfuration pathway (2Wang L. Jhee K.H. Hua X. DiBello P.M. Jacobsen D.W. Kruger W.D. Circ. Res. 2004; 94: 1318-1324Crossref PubMed Scopus (82) Google Scholar). When Hcy metabolism is impaired, an increase in its concentration in the blood occurs, a condition termed hyperhomocysteinemia. Regarded as a risk factor for cardiovascular and cerebral vascular diseases (3Lentz S.R. J. Thromb. Haemost. 2005; 3: 1646-1654Crossref PubMed Scopus (306) Google Scholar, 4Refsum H. Ueland P.M. Nygård O. Vollset S.E. Annu. Rev. Med. 1998; 49: 31-62Crossref PubMed Scopus (1829) Google Scholar, 5Wald D.S. Law M. Morris J.K. BMJ. 2002; 325: 1202Crossref PubMed Scopus (1677) Google Scholar), Hcy, at elevated levels, also affects the function of other organs such as liver and kidney (6Distrutti E. Mencarelli A. Santucci L. Renga B. Orlandi S. Donini A. Shah V. Fiorucci S. Hepatology. 2008; 47: 659-667Crossref PubMed Scopus (54) Google Scholar, 7Yi F. Li P.L. Am. J. Nephrol. 2008; 28: 254-264Crossref PubMed Scopus (83) Google Scholar). The kidney plays an important role in regulating Hcy concentrations in the circulation. It is estimated that the kidney is responsible for the removal of ∼20% of Hcy from the systemic circulation (8House J.D. Brosnan M.E. Brosnan J.T. Biochem. J. 1997; 328: 287-292Crossref PubMed Scopus (100) Google Scholar). Metabolism of Hcy in the kidney (up to 78%) is primarily through the trans-sulfuration pathway, in which the CBS enzyme regulates the rate-limiting step by condensing Hcy with serine to form cystathionine (8House J.D. Brosnan M.E. Brosnan J.T. Biochem. J. 1997; 328: 287-292Crossref PubMed Scopus (100) Google Scholar). Impaired kidney function is inversely correlated with the Hcy level in the circulation (9Francis M.E. Eggers P.W. Hostetter T.H. Briggs J.P. Kidney Int. 2004; 66: 303-312Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). CBS is also responsible for the endogenous synthesis of H2S from cysteine and Hcy through a β-replacement reaction (10Singh S. Padovani D. Leslie R.A. Chiku T. Banerjee R. J. Biol. Chem. 2009; 284: 22457-22466Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 11Chen X. Jhee K.H. Kruger W.D. J. Biol. Chem. 2004; 279: 52082-52086Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). H2S has recently emerged as an important biologically active compound in human health and disease. At physiological concentrations, H2S acts as an essential gaseous neurotransmitter (12Moore P.K. Bhatia M. Moochhala S. Trends Pharmacol. Sci. 2003; 24: 609-611Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar) and has the ability to attenuate myocardial ischemia/reperfusion injury in animal models (13Elrod J.W. Calvert J.W. Morrison J. Doeller J.E. Kraus D.W. Tao L. Jiao X. Scalia R. Kiss L. Szabo C. Kimura H. Chow C.W. Lefer D.J. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 15560-15565Crossref PubMed Scopus (890) Google Scholar). A decrease in H2S production leads to various diseases including Alzheimer disease (14Eto K. Asada T. Arima K. Makifuchi T. Kimura H. Biochem. Biophys. Res. Commun. 2002; 293: 1485-1488Crossref PubMed Scopus (659) Google Scholar), atherosclerosis (15Wang Y. Zhao X. Jin H. Wei H. Li W. Bu D. Tang X. Ren Y. Tang C. Du J. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 173-179Crossref PubMed Scopus (254) Google Scholar), and portal hypertension (6Distrutti E. Mencarelli A. Santucci L. Renga B. Orlandi S. Donini A. Shah V. Fiorucci S. Hepatology. 2008; 47: 659-667Crossref PubMed Scopus (54) Google Scholar). Our recent study indicates that a reduction of endogenous H2S production is associated with kidney ischemia/reperfusion injury (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar). Because of the critical roles of CBS in regulating Hcy and H2S levels, it is of great importance to understand the that CBS active form of the CBS enzyme is a that is of M. M. V. Kraus J.P. J. PubMed Scopus Google Scholar). of the amino the central amino and the amino The CBS activity is regulated at the transcriptional and studies the transcriptional of human CBS mRNA which and form the of and has the activity J.P. J. J. Kraus E. C. R. L. D. V. W. V. 1998; PubMed Scopus Google Scholar, L. C. V. Kraus J.P. Biochem. Biophys. 1998; PubMed Scopus Google Scholar). transcription factor and factor as for the human Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.W. Biochem. J. PubMed Scopus Google Scholar, Kraus E. Kraus J.P. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The of has in human cells to be responsible for the of activity Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.W. Biochem. J. PubMed Scopus Google Scholar). to the of rat there are two in the of the CBS gene Kraus E. J. M. Kraus J.P. PubMed Scopus Google Scholar). is the transcriptional of CBS expression in ischemia/reperfusion injury is by in the which leads to a of and Ischemia/reperfusion injury is a of decreased blood to the followed by of blood to the is a in with kidney disease renal J. J. Am. Nephrol. PubMed Google Scholar). investigated the role of CBS in Hcy and H2S metabolism in a rat with kidney ischemia/reperfusion (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar, Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar, Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). Ischemia/reperfusion a reduction of CBS activity leading to Hcy accumulation in the kidney Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). Hcy, at elevated levels, and cell in the kidney Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar). also that ischemia/reperfusion leads to a reduction of H2S levels in the kidney (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar). of H2S cell and kidney function (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar, Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar). and accumulation to the reduced CBS activity in the kidney, the of and removal of CBS activity Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). may be in the of CBS activity in the of the study was to the molecular mechanism by which CBS expression was regulated in the kidney during ischemia/reperfusion injury. Our results that ischemia/reperfusion caused a reduction of CBS mRNA gene expression leading to a decrease in CBS protein levels and enzyme activity. that reduction in CBS expression was to a decrease in the transcriptional by transcription factor of in phosphorylation of which for decreased transcriptional of CBS gene expression in the kidney during plays an important role in the homeostasis of Hcy and H2S in of CBS activity can to an in Hcy and H2S The results from the study a mechanism by which CBS is regulated in the kidney during ischemia/reperfusion. Sp1 is to play an important role in the transcriptional of CBS gene expression in the kidney. phosphorylation of Sp1 is mediated via which in turn to a reduced activity of Sp1 and a decrease in the CBS gene As a consequence, there is a significant decrease in CBS enzyme an of the Hcy level and a of the H2S level in the CBS activity is regulated at the transcriptional Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.W. Biochem. J. PubMed Scopus Google Scholar) and Banerjee R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) In the upon the CBS mRNA and protein levels in the kidney A reduction of CBS expression was also detected in kidney proximal tubular cells. of that Sp1 was in the of CBS gene expression in the kidney. the that the activity of Sp1 was reduced in the kidney upon ischemia/reperfusion. results from the chromatin immunoprecipitation assay a significant decrease in the of Sp1 to the of CBS gene in the kidney subjected to ischemia/reperfusion. the role of Sp1 in the transcriptional of CBS gene expression was investigated in tubular cells that with Sp1 of Sp1 caused a marked reduction of CBS gene expression in cells. a transcriptional such as factor and factor to the expression of the human CBS gene Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), two Sp1 in the of the CBS gene Kraus E. J. M. Kraus J.P. PubMed Scopus Google Scholar). is the of CBS expression in The results from the study that Sp1 an important role in regulating CBS gene expression in the rat kidney. transcriptional activity of Sp1 upon ischemia/reperfusion to a significant reduction of CBS expression in the is a acid transcription factor that the in the of D. S.Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). As in the the critical and role of Sp1 in the of rat CBS expression in the kidney is in with its role in regulating human CBS expression in other cells in studies Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Kraus E. Kraus J.P. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kraus E. V. Kraus J.P. J. Physiol. 2002; PubMed Scopus Google Scholar). such as phosphorylation and as important in the of Sp1 to the of G. A. J. A. R. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 2009; 29: PubMed Scopus Google Scholar). Sp1 protein can be at various leading to in the and its transcriptional activity C. J. B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 2009; 29: PubMed Scopus Google Scholar, D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Sp1 has phosphorylation with of and Biol. 2009; 29: PubMed Scopus Google Scholar). in human and Sp1 to be the for phosphorylation D. S.Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. 2008; PubMed Scopus Google Scholar). It has in the and that phosphorylation of Sp1 leads to a decrease in the activity and a reduction of the transcriptional activity C. J. B. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation of Sp1 may to a decrease in its transcriptional activity. It has that Sp1 phosphorylation an increase in the activity in rat cells S. A. M. A. S. Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of and transcriptional activity by phosphorylation may be and ischemia/reperfusion the phosphorylation of Sp1 in the kidney, we an immunoprecipitation with followed by with of Sp1 was in the kidney subjected to ischemia/reperfusion. It has that phosphorylation of Sp1 can be through such as in of cells and in various disease models J. J. G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, E. G. O. W. F. 2004; 104: PubMed Scopus Google Scholar, K. Res. 2007; PubMed Scopus Google Scholar). which pathway is in the phosphorylation of Sp1 In the the activity was elevated in the kidney subjected to ischemia/reperfusion. of tubular cells with an that activity also CBS expression in cells. results that an ERK-mediated phosphorylation in Sp1 of the that for a reduction of activity and a decrease in CBS expression in the kidney upon is a enzyme in which is a associated with its M. M. V. Kraus J.P. J. PubMed Scopus Google Scholar). acts as a to CBS and in the of can CBS activity Banerjee R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. X. Kruger W.D. Banerjee R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). to physiological in the CBS is in the at is in the which in the active form of CBS S. J. Kraus J.P. 2004; PubMed Scopus Google Scholar). detected a CBS activity in the kidney with levels from to and the enzyme activity was at Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). The is decreased in the kidney during the ischemia of which in turn a significant reduction of CBS activity Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). of by an the CBS activity and cell Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). from there is a marked increase in production in the kidney during the Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). can with the in the CBS an of CBS activity Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar, S. Banerjee R. J. Biochem. PubMed Scopus Google Scholar). In a we that during the the in the kidney the CBS to Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). of the CBS activity and Hcy levels Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar) and H2S levels (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar) in the kidney. of and of are to ischemia/reperfusion CBS activity Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). These results that be in the of CBS activity in the kidney. The results from the study that reduced CBS gene expression an important molecular mechanism responsible for the reduction of CBS activity in the kidney upon which in turn to an accumulation of Hcy and a reduction of H2S in the kidney (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar, Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar, Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google the for the has a mechanism for a reduced CBS expression in the kidney during ischemia/reperfusion. Sp1 phosphorylation via in a decreased Sp1 transcriptional of CBS gene expression in the kidney upon ischemia/reperfusion. As a consequence, the CBS-mediated Hcy and H2S metabolism is impaired, leading to a significant increase in the Hcy level and a marked decrease in the H2S level in the kidney. an in Hcy and H2S homeostasis to kidney injury. the that CBS activity the function of this enzyme in Hcy and H2S homeostasis in the kidney. IntroductionHomocysteine (Hcy) 2The abbreviations used are: HcyhomocysteineCBScystathionine β-synthaseChIPchromatin immunoprecipitation assayEMSAelectrophoretic mobility shift assayGAPDHglyceraldehyde-3-phosphate dehydrogenasesiRNAsmall interfering RNAERKextracellular signal-regulated kinaseMAPmitogen-activated protein kinase. and H2S are two important molecules produced in the body during the metabolism of sulfur amino acids. Cystathionine β-synthase (CBS, EC 4.2.1.22) is a key enzyme that regulates the metabolism of Hcy and H2S (1Eto K. Kimura H. J. Biol. Chem. 2002; 277: 42680-42685Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Hcy is an intermediate amino acid formed during the conversion of methionine to cysteine and is central to the supply of methyl groups that are critical to normal cell function. Hcy can be metabolized via two major pathways, namely the remethylation pathway (remethylation of Hcy to methionine) and the trans-sulfuration pathway (trans-sulfuration of Hcy to cysteine) (2Wang L. Jhee K.H. Hua X. DiBello P.M. Jacobsen D.W. Kruger W.D. Circ. Res. 2004; 94: 1318-1324Crossref PubMed Scopus (82) Google Scholar). CBS catalyzes the rate-limiting step in the trans-sulfuration pathway (2Wang L. Jhee K.H. Hua X. DiBello P.M. Jacobsen D.W. Kruger W.D. Circ. Res. 2004; 94: 1318-1324Crossref PubMed Scopus (82) Google Scholar). When Hcy metabolism is impaired, an increase in its concentration in the blood occurs, a condition termed hyperhomocysteinemia. Regarded as a risk factor for cardiovascular and cerebral vascular diseases (3Lentz S.R. J. Thromb. Haemost. 2005; 3: 1646-1654Crossref PubMed Scopus (306) Google Scholar, 4Refsum H. Ueland P.M. Nygård O. Vollset S.E. Annu. Rev. Med. 1998; 49: 31-62Crossref PubMed Scopus (1829) Google Scholar, 5Wald D.S. Law M. Morris J.K. BMJ. 2002; 325: 1202Crossref PubMed Scopus (1677) Google Scholar), Hcy, at elevated levels, also affects the function of other organs such as liver and kidney (6Distrutti E. Mencarelli A. Santucci L. Renga B. Orlandi S. Donini A. Shah V. Fiorucci S. Hepatology. 2008; 47: 659-667Crossref PubMed Scopus (54) Google Scholar, 7Yi F. Li P.L. Am. J. Nephrol. 2008; 28: 254-264Crossref PubMed Scopus (83) Google Scholar). The kidney plays an important role in regulating Hcy concentrations in the circulation. It is estimated that the kidney is responsible for the removal of ∼20% of Hcy from the systemic circulation (8House J.D. Brosnan M.E. Brosnan J.T. Biochem. J. 1997; 328: 287-292Crossref PubMed Scopus (100) Google Scholar). Metabolism of Hcy in the kidney (up to 78%) is primarily through the trans-sulfuration pathway, in which the CBS enzyme regulates the rate-limiting step by condensing Hcy with serine to form cystathionine (8House J.D. Brosnan M.E. Brosnan J.T. Biochem. J. 1997; 328: 287-292Crossref PubMed Scopus (100) Google Scholar). Impaired kidney function is inversely correlated with the Hcy level in the circulation (9Francis M.E. Eggers P.W. Hostetter T.H. Briggs J.P. Kidney Int. 2004; 66: 303-312Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). CBS is also responsible for the endogenous synthesis of H2S from cysteine and Hcy through a β-replacement reaction (10Singh S. Padovani D. Leslie R.A. Chiku T. Banerjee R. J. Biol. Chem. 2009; 284: 22457-22466Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, 11Chen X. Jhee K.H. Kruger W.D. J. Biol. Chem. 2004; 279: 52082-52086Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). H2S has recently emerged as an important biologically active compound in human health and disease. At physiological concentrations, H2S acts as an essential gaseous neurotransmitter (12Moore P.K. Bhatia M. Moochhala S. Trends Pharmacol. Sci. 2003; 24: 609-611Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar) and has the ability to attenuate myocardial ischemia/reperfusion injury in animal models (13Elrod J.W. Calvert J.W. Morrison J. Doeller J.E. Kraus D.W. Tao L. Jiao X. Scalia R. Kiss L. Szabo C. Kimura H. Chow C.W. Lefer D.J. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 15560-15565Crossref PubMed Scopus (890) Google Scholar). A decrease in H2S production leads to various diseases including Alzheimer disease (14Eto K. Asada T. Arima K. Makifuchi T. Kimura H. Biochem. Biophys. Res. Commun. 2002; 293: 1485-1488Crossref PubMed Scopus (659) Google Scholar), atherosclerosis (15Wang Y. Zhao X. Jin H. Wei H. Li W. Bu D. Tang X. Ren Y. Tang C. Du J. Arterioscler. Thromb. Vasc. Biol. 2009; 29: 173-179Crossref PubMed Scopus (254) Google Scholar), and portal hypertension (6Distrutti E. Mencarelli A. Santucci L. Renga B. Orlandi S. Donini A. Shah V. Fiorucci S. Hepatology. 2008; 47: 659-667Crossref PubMed Scopus (54) Google Scholar). Our recent study indicates that a reduction of endogenous H2S production is associated with kidney ischemia/reperfusion injury (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar). Because of the critical roles of CBS in regulating Hcy and H2S levels, it is of great importance to understand the that CBS active form of the CBS enzyme is a that is of M. M. V. Kraus J.P. J. PubMed Scopus Google Scholar). of the amino the central amino and the amino The CBS activity is regulated at the transcriptional and studies the transcriptional of human CBS mRNA which and form the of and has the activity J.P. J. J. Kraus E. C. R. L. D. V. W. V. 1998; PubMed Scopus Google Scholar, L. C. V. Kraus J.P. Biochem. Biophys. 1998; PubMed Scopus Google Scholar). transcription factor and factor as for the human Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.W. Biochem. J. PubMed Scopus Google Scholar, Kraus E. Kraus J.P. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The of has in human cells to be responsible for the of activity Y. J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.W. Biochem. J. PubMed Scopus Google Scholar). to the of rat there are two in the of the CBS gene Kraus E. J. M. Kraus J.P. PubMed Scopus Google Scholar). is the transcriptional of CBS expression in ischemia/reperfusion injury is by in the which leads to a of and Ischemia/reperfusion injury is a of decreased blood to the followed by of blood to the is a in with kidney disease renal J. J. Am. Nephrol. PubMed Google Scholar). investigated the role of CBS in Hcy and H2S metabolism in a rat with kidney ischemia/reperfusion (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar, Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar, Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). Ischemia/reperfusion a reduction of CBS activity leading to Hcy accumulation in the kidney Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). Hcy, at elevated levels, and cell in the kidney Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar). also that ischemia/reperfusion leads to a reduction of H2S levels in the kidney (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar). of H2S cell and kidney function (16Xu Z. Prathapasinghe G. Wu N. Hwang S.Y. Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2009; 297: F27-F35Crossref PubMed Scopus (94) Google Scholar, Siow Y.L. O K. Am. J. Physiol. Renal Physiol. 2007; PubMed Scopus Google Scholar). and accumulation to the reduced CBS activity in the kidney, the of and removal of CBS activity Siow Y.L. Z. O K. Am. J. Physiol. Renal Physiol. 2008; PubMed Scopus Google Scholar). may be in the of CBS activity in the of the study was to the molecular mechanism by which CBS expression was regulated in the kidney during ischemia/reperfusion injury. Our results that ischemia/reperfusion caused a reduction of CBS mRNA gene expression leading to a decrease in CBS protein levels and enzyme activity. that reduction in CBS expression was to a decrease in the transcriptional by transcription factor of in phosphorylation of which for decreased transcriptional of CBS gene expression in the kidney during ischemia/reperfusion.

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