Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Li, Ningjun; Chen, Li; Muh, Rachel; Li, Pin‐Lan

doi:10.1161/01.hyp.0000219634.83928.6e

Cited by 40 publications

(31 citation statements)

References 39 publications

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“…Although blood pressure elevation in these animals is attributed to abnormal regulation of vascular tone, it cannot be excluded that impaired H 2 S effects in the kidney, including its effects on renal oxygenation, contribute to the observed phenotype. Although renal H 2 S pro- jpet.aspetjournals.org duction was not measured in other models of hypertension, CBS expression and activity are markedly reduced in the kidney of Dahl salt-sensitive hypertensive rats (Li et al, 2006). It should be noted that deficiency of other vasodilators in the renal medulla induced by local infusion of NO synthase, cyclooxygenase, or HO-1 inhibitors induces hypertension in experimental animals by increasing tubular Na ϩ reabsorption.…”

Section: H 2 S and Renal Oxygenation In Hypertensionmentioning

confidence: 93%

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Bełtowski

2010

J Pharmacol Exp Ther

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Hydrogen sulfide (H 2 S) is enzymatically generated in mammalian tissues from either L-cysteine or L-homocysteine. H 2 S possesses multiple biological activities, including regulation of vascular tone and blood pressure. Hydrogen sulfide produced in endothelial cells, vascular smooth muscle cells, and perivascular adipose tissue dilates blood vessels by activating ATP-sensitive potassium channels. In addition, H 2 S produced locally within the kidney stimulates natriuresis and diuresis by increasing glomerular filtration and inhibiting tubular sodium reabsorption. Because H 2 S is oxidized in mitochondria in pO 2 -dependent manner and ambient pO 2 is physiologically low in the renal medulla, it is expected that the activity of H 2 S is higher in the medullary region than the cortical region. H 2 S, accumulating in increased amounts in the renal medulla under hypoxic conditions, may function as an oxygen sensor that restores O 2 balance by increasing medullary blood flow, reducing energy requirements for tubular transport, and directly inhibiting mitochondrial respiration. Hypoxia is an important pathogenic factor in many renal diseases, such as ischemia/reperfusion-or nephrotoxin-induced acute renal failure, progression of chronic nephropathies, diabetic nephropathy, and arterial hypertension. Deficiency of endogenous H 2 S may contribute to the pathogenesis of these pathologies by compromising medullary oxygenation, and administration of H 2 S donors may be of therapeutic value in these disorders.Studies performed during the last decade indicate that, apart from NO and CO, H 2 S is the third "gasotransmitter" involved in the regulation of various physiological functions, including vascular tone and blood pressure, inflammatory reaction, neurotransmission and gastrointestinal system function. H 2 S is enzymatically synthesized in three metabolic pathways (Fig. 1): 1) desulfhydration of L-cysteine or L-homocysteine by cystathionine ␥-lyase (CSE, EC 4.4.1.1), 2) desulfhydration of L-cysteine by cystathionine ␤-synthase (CBS, EC 4.2.1.22), and 3) transamination of L-cysteine by cysteine aminotransferase (identical with aspartate aminotransferase) to 3-mercaptopyruvate, followed by its desulfhydration to pyruvate by 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.2). Hydrogen sulfide activates ATP-sensitive potassium channels (K ATP ) in various cells, although many other signaling mechanisms have also been described. H 2 S is inactivated by binding to hemoglobin to form sulfhemoglobin, excretion in exhaled air, and, first and foremost, oxidation in mitochondria. Many studies addressed the role of H 2 S in the regulation of vascular tone and blood pressure. Indeed, it is suggested that H 2 S deficiency may contribute to the pathogenesis of arterial hypertension both in experimental animal models and in humans. Recently, renal synthesis and activity of H 2 S have been characterized (Xia et al., 2009). Because renal sodium handling has a prominent role in the long-term regulation of blood pressure (apart...

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Section: H 2 S and Renal Oxygenation In Hypertensionmentioning

confidence: 93%

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Bełtowski

2010

J Pharmacol Exp Ther

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“…Total RNA from renal cortical and medullary tissues was extracted using TRIzol solution (Life Technologies, Rockville, MD) and then reverse-transcribed (RT; cDNA Synthesis Kit, Bio-Rad, Hercules, CA) (19). The RT products were amplified using real-time quantitative PCR kits.…”

Section: Animalsmentioning

confidence: 99%

A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate

Zhu

Xia

Wang

et al. 2011

American Journal of Physiology-Renal Physiology

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Zhu Q, Xia M, Wang Z, Li P, Li N. A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate. Am J Physiol Renal Physiol 301: F35-F41, 2011. First published April 6, 2011 doi:10.1152/ajprenal.00014.2011.-Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine. S1P has been indicated to play a significant role in the cardiovascular system. It has been shown that the enzymes for S1P metabolism are expressed in the kidneys. The present study characterized the expression of S1P receptors in the kidneys and determined the role of S1P in the control of renal hemodynamics and sodium excretion. Real-time RT-PCR analyses showed that S1P receptors S1P1, S1P2, and S1P3 were most abundantly expressed in the renal medulla. Immunohistochemistry revealed that all three types of S1P receptors were mainly located in collecting ducts. Intramedullary infusion of FTY720, an S1P agonist, produced a dramatic increase in sodium excretion by twofold and a small but significant increase in medullary blood flow (16%). Administration of W146, an S1P1 antagonist, into the renal medulla blocked the effect of FTY720 and decreased the sodium excretion by 37% when infused alone. The antagonists of S1P2 and S1P3 had no effect. FTY720 produced additive natriuretic effects in combination with different sodium transporter inhibitors except amiloride, an epithelial sodium channel blocker. In the presence of nitric oxide synthase inhibitor L-NAME, FTY720 still increased sodium excretion. These data suggest that S1P produces natriuretic effects via activation of S1P1 in the renal medulla and this natriuretic effect may be through inhibition of epithelial sodium channel, which is nitric oxide independent. It is concluded that S1P is a novel diuretic factor in the renal medulla and may be an important regulator of sodium homeostasis. renal blood flow; sodium transporter; nitric oxide; collecting duct SPHINGOLIPIDS WERE ORIGINALLY thought to serve only as structural components of mammalian cell membranes. In recent years, sphingolipid metabolites are emerging as important lipid signaling molecules. Among them, sphingosine-1-phosphate (S1P) is known to play important roles in cellular processes in various organ systems including cardiovascular system and kidney (15,29). S1P is formed by phosphorylation of sphingosine catalyzed by sphingosine kinase and acts via its G protein-coupled receptors (17,29). Five members of S1P receptor family have been identified and termed S1P1-S1P5 (17, 29). The S1P1, S1P2, and S1P3 are ubiquitously expressed, while S1P4 is predominantly expressed in the lung and lymphoid system, and S1P5 is mainly in brain tissue (17,29). The expression and activity of sphingosine kinase have been detected in the kidneys (1, 10) and the mRNAs of S1P receptors are also present in the kidneys (17). It has been shown that S1P protects the kidneys from ischemic injury (2,27). It has also been demonstrated that S1P regulates vascular functions (14, 23). Therefore, it is p...

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“…Although two enzymes are involved in this metabolic pathway of Hcys, CBS is rate limiting in this transsulfuration metabolism of Hcys. In the kidney, Hcys is primarily transsulfurated, and deficiency of this renal transulfuration importantly contributes to the elevation of plasma Hcys under different physiological or pathological conditions, such as hypertension, diabetes mellitus, aging, or ESRD [14, 15]. …”

Section: Homocysteine (Hcys) Metabolism and Hyperhomocysteinemia (Hhcys)mentioning

confidence: 99%

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

Li²

2007

Am J Nephrol

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Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as lo- cal oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.

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Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Cited by 40 publications

References 39 publications

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

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