Downregulation of cystathionine<i>β</i>-synthase and cystathionine<i>γ</i>-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury

Wang, Pengqi; Isaak, Cara K.; Siow, Yaw L.; Karmin, O

doi:10.14814/phy2.12251

Cited by 39 publications

(43 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The transsulfuration pathway enzymes are widely present in mammalian tissues such as liver, kidney, intestine, heart, aorta, brain, lungs, and intestine, with liver having high enzyme activity of both CBS and CSE [14, 33–38]. Our recent study has shown that IR downregulates the expression of transsulfuration enzymes in the kidney, leading to increased oxidative stress and inflammatory response [39]. Although liver oxidative stress has been reported in ischemic AKI, the mechanism by which renal IR impairs hepatic glutathione production is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Shang

Siow

Isaak

et al. 2016

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion.

show abstract

Section: Introductionmentioning

confidence: 99%

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Shang

Siow

Isaak

et al. 2016

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

show abstract

“…Głów-nym substratem syntezy endogennego siarkowodoru jest L-cysteina, a enzymy katalizujące reakcje syntezy to β-syntaza cystationiny (cystathionine β-synthase -CBS) oraz γ-liaza cystationiny (cystathionine γ-lyase -CSE), oba zależne od kofaktora -fosforanu pirydoksalu. Oba enzymy -CBS i CSE -są także odpowiedzialne za syntezę cysteiny, prekursora glutationu, głównego związku o działaniu antyoksydacyjnym [9,13].…”

Section: Materiał I Metodyunclassified

“…Beta-syntaza cystationiny znajduje się głównie w komórkach centralnego układu nerwowego, zwłaszcza w neuronach hipokampa i komórkach Purkinyego oraz w nerkach, wątrobie, komórkach jelit, wysp trzustkowych, łożysku i macicy [13,14]. Gamma-liaza cystationiny obecna jest przede wszystkim w komórkach mię-śni gładkich ściany naczyń krwionośnych i mięśniu sercowym, a także w wątrobie, nerkach, jelicie, macicy, mózgu, trzustce i łożysku.…”

Section: Materiał I Metodyunclassified

“…Aktywność CBS jest regulowana na poziomie transkrypcyjnym przez różne czynniki ją-drowe, czynniki wzrostu i cykliczny adenozynomonofosforan oraz na poziomie posttranskrypcyjnym przez np. metioninę [13]. Z kolei siarkowodór hamuje aktywność enzymów odpowiedzialnych za jego syntezę (CBS i CSE) w mechanizmie ujemnego sprzężenia zwrot-nego [9].…”

Section: Omówienieunclassified

“…Zmiany regulacyjne przebiegają-ce ze wzrostem stężenia CBS i CSE towarzyszą zwięk-szonej syntezie endogennego H 2 S [13]. Wyjaśnienia wymaga, czy zmiany te mogą towarzyszyć powtarzanej ekspozycji na H 2 S, a jeśli tak, czy są związane z obecnością siarkowodoru, czy z przerwą w ekspozycji na H 2 S.…”

unclassified

See 2 more Smart Citations

Serum cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE ) and cytochrome c oxidase (COX) in copper mine miners potentially expose d to hydrogen sulfide

Skoczyńska¹,

Gruszczyński²,

Turczyn³

et al. 2015

Med Pr

View full text Add to dashboard Cite

StreszczenieWstęp: Celem badań była ocena stężenia mitochondrialnego enzymu docelowego dla toksycznego działania siarkowodoru, tj. oksydazy cytochromu c (COX) oraz enzymów uczestniczących w syntezie endogennego H 2 S (siarkowodoru) -syntazy β-cystationiny (CBS) i γ-liazy cystationiny (CSE) w surowicy górników kopalni miedzi. Materiał i metody: Badanie wstępne przeprowadzono u 237 górników, a zasadnicze u 88 górników zatrudnionych w 2 szybach: I -bez zarejestrowanych emisji H 2 S w ciągu ostatnich 10 lat (grupa badana A); II -w którym występowały emisje H 2 S (grupa badana B). U górników przeprowadzono badania lekarskie i bezpośrednio po wyjeździe z kopalni na powierzchnię pobrano od nich po 10 ml krwi żylnej. Wyniki: Nie stwierdzono żadnych zmian klinicznych ani biochemicznych, typowych dla toksycznego działania siarkowodoru. Stężenie sulfhemoglobiny było nieoznaczalne, nie stwierdzono zmian w układzie oksydo-redukcyjnym. W grupie B wykazano natomiast zmiany regulacyjne, które mogą być wynikiem powtarzanych ekspozycji na H 2 S. Do tych zmian należy wyższe stężenie CBS i CSE w surowicy, wzrost aktywności enzymu konwertującego angiotensynę (ACE) w porównaniu z grupą A oraz liniowa zależ-ność między ACE a CSE (r = 0,6927; p < 0,001). Wykazano, że palenie papierosów obniża stężenie COX (p < 0,05), jednak u gór-ników zatrudnionych w szybie II obniżenie stężenia COX może wynikać, poza paleniem, także z obecności siarkowodoru w gazach kopalnianych. Wnioski: Stężenie COX może być czułym wskaźnikiem ekspozycji na siarkowodór. Pomiary stężenia siarkowodoru we krwi przeprowadzane na stanowiskach pracy powinny wyjaśnić przyczynę zmian w aktywności COX, CBS i CSE. Med. Pr. 2015;66(4):539-548 Słowa kluczowe: górnicy, siarkowodór, oksydaza cytochromu c, β-syntaza cystationiny, γ-liaza cystationiny, kopalnia miedzi Abstract Background: The aim of the study was to evaluate serum levels of the target enzyme for H 2 S toxicity -cytochrome c oxidase (COX) and enzymes involved in the synthesis of H 2 S -cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) in copper mine miners. Material and Methods: The initial and basic study was conducted respectively in 237 and 88 miners, working in 2 mining shafts: I -no H 2 S emissions recorded in the last 10 years (study group A) and II -H 2 S emissions occurred (study group B). A medical examination was performed and 10 ml of blood was collected from miners immediately after exiting the mine. Results: There were no clinical or biochemical changes typical for H 2 S toxicity. Sulfhemoglobine was undetectable and there were no changes in the red-ox system. However, in group B, regulatory changes were found; a tendency to higher concentration of CBS and CSE, a higher activity of angiotensin converting enzyme (ACE) compared to group A (p < 0.05) and a linear relationship between ACE and CSE (r = 0.6927; p < 0.001). It has been shown that cigarette smoking decreases COX (p < 0.05), however, in miners working in shaft II, the decreased level of COX may result also from the presence of H 2 ...

show abstract

Cystathionine β‐synthase is required for body iron homeostasis

Zhou

Zhang

et al. 2017

Hepatology

View full text Add to dashboard Cite

Cystathionine b-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS 2/2 ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBSoverexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Conclusion: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosislike phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (HEPATOLOGY 2018;67:21-35) C ystathionine b-synthase (CBS) was first isolated in the liver by Braunstein et al.(1) in 1969. The location of the human CBS gene is on chromosome 21 (43.35-43.37 Mb).(2) CBS is a key enzyme for hydrogen sulfide (H 2 S) production from L-cysteine, in addition to cystathionine gammalyase and 3-mercaptopyruvate sulfurtransferase. (2,3) H 2 S has been implicated as the third endogenous gas transmitter, after nitric oxide and carbon monoxide, functioning in the brain as well as peripheral organs.(2,3) CBS deficiency, induced by mutation in the CBS gene, is a rare autosomal recessive disorder characterized by highly elevated levels of total plasma homocysteine.(4) Patients not treated in infancy have multisystem disorders including arterial occlusions, venous thromboembolisms, osteoporosis, intellectual disabilities, psychiatric disorders, and dislocated lenses.(4,5) Homozygous knockout mice (CBS 2/2 ) rarely survive past 4 weeks of age, (2) implying that CBS is essential for survival and development in mice. It has been demonstrated that H 2 S has a significant effect on the regulation of proinflammatory cytokines including interleukin-6 (IL-6) (6) and signal transducer and activator of transcription 3 (STAT3) activity. (7)(8)(9)(10) Abbreviations: Ad, adenovirus; BMDM, bone marrow-derived macrophage; CBS, cystathionine b-synthase; 9 (11) -dien-28-oyl] imidazole; DMT1, d...

show abstract

Downregulation of cystathionineβ-synthase and cystathionineγ-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury

Cited by 39 publications

References 50 publications

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

Serum cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE ) and cytochrome c oxidase (COX) in copper mine miners potentially expose d to hydrogen sulfide

Cystathionine β‐synthase is required for body iron homeostasis

Contact Info

Product

Resources

About