s-adenosylhomocysteine and Kidney-Diseases

Transmethylation reactions utilize S-adenosylmethionine (SAM) as a methyl donor and are central to the regulation of many biological processes: more than fifty SAM-dependent methyltransferases methylate a broad spectrum of cellular compounds including DNA, histones, phospholipids and other small molecules. Common to all SAM-dependent transmethylation reactions is the release of the potent inhibitor S-adenosylhomocysteine (SAH) as a by-product. SAH is reversibly hydrolyzed to adenosine and homocysteine by SAH hydrolase. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. However, a major unanswered question is if homocysteine is causally involved in disease pathogenesis or simply a passive and indirect indicator of a more complex mechanism. A chronic elevation in homocysteine levels results in a parallel increase in intracellular or plasma SAH, which is a more sensitive biomarker of cardiovascular disease than homocysteine and suggests that SAH is a critical pathological factor in homocysteine-associated disorders. Previous reports indicate that supplementation with folate and B vitamins efficiently lowers homocysteine levels but not plasma SAH levels, which possibly explains the failure of homocysteine-lowering vitamins to reduce vascular events in several recent clinical intervention studies. Furthermore, more studies are focusing on the role and mechanisms of SAH in different chronic diseases related to hyperhomocysteinemia, such as cardiovascular disease, kidney disease, diabetes, and obesity. This review summarizes the current role of SAH in cardiovascular disease and its effect on several related risk factors. It also explores possible the mechanisms, such as epigenetics and oxidative stress, of SAH. This article is part of a Directed Issue entitled: Epigenetic dynamics in development and disease.

Topics: Atherosclerosis; Diabetes Mellitus; Endothelium, Vascular; Epigenesis, Genetic; Humans; Hyperhomocysteinemia; Kidney Diseases; Obesity; Oxidative Stress; S-Adenosylhomocysteine; S-Adenosylmethionine

Qian Yang Yu Yin Granule (QYYY) is a Chinese herbal formulation. It is used to treat hypertensive nephropathy for decades in China, but it is unknown that the exact mechanism of QYYY on hypertensive nephropathy.. The present study was to elucidate its epigenetic mechanism of QYYY on hypertensive nephropathy.. In the current study, HEK293T cells' proliferation induced by Ang II was chosen to observe epigenetic mechanisms of QYYY on renal damage. The cell proliferation was examined by MTT assays and ethynyldeoxyuridine analysis. Cell cycle analysis was performed. After treatment with QYYY, expression of Nicotinamide N-methyltransferase (NNMT), sirtuin1(SIRT1), S-adenosylhomocysteine(SAH), histone H3K4 methylation, and cortactin acetylation(acetyl-cortactin,ac-cortactin) were further investigated by western-blotting and real time PCR. DNA methylation was detected by ELISA. The study also observed the changes of SIRT1, SAH, H3K4 methylation, acetyl-cortactin when NNMT over-expressed by lentivirus transfection. Angiotensin II(Ang II) induced renal damage in spontaneously hypertensive rats(SHR). After eight weeks treatment of QYYY, blood pressure, serum and urine creatinine, and urinary microalbumin(mAlb) were assessed. The concentration of N1 -methylnicotinamide were detected by liquid chromatography with tandem mass spectrometry. The protein of NNMT, ac-cortactin, H3K3me3 were also assessed in vivo.. QYYY inhibited HEK293T cells' proliferation, down-regulated the expression of NNMT, SAH, acetyl-cortactin and DNA methylation, up-regulated the expression of SIRT1, histone H3K4 trimethylation(H3K4me3). Over-expression of NNMT increased the expression of SAH and acetyl-cortactin, and reduced the expression of SIRT1 and H3K4me3. The study also demonstrated that QYYY promoted urinary creatinine excretion and reduced serum creatinine and urinary mAlb in SHR. QYYY decreased the concentration of N1 -methylnicotinamide in Ang II group. QYYY decreased the protein of NNMT, ac-cortactin and increased H3K4me3 in vivo.. The results showed that QYYY alleviated renal impairment of SHR and inhibited HEK293T cells' proliferation induced by Ang II through the pathway of epigenetic mechanism linked to Nicotinamide N-Methyltransferase (NNMT) expression, including histone methylation, DNA methylation and acetyl-cortactin. This study unveiled a novel molecular mechanism by which QYYY controlled the progression of hypertensive nephropathy.

Topics: Acetylation; Angiotensin II; Animals; Cell Proliferation; Cortactin; Disease Models, Animal; DNA Methylation; Drugs, Chinese Herbal; Epigenesis, Genetic; Epithelial Cells; HEK293 Cells; Histones; Humans; Hypertension; Kidney; Kidney Diseases; Male; Nicotinamide N-Methyltransferase; Rats, Inbred SHR; Rats, Inbred WKY; S-Adenosylhomocysteine; Sirtuin 1

The putative role of sulfur amino acids such as homocysteine (tHcy) as cardiovascular risk factors is controversial in chronic kidney disease (CKD). Although, S-adenosylhomocysteine (SAH) levels have been linked to CVD in non-renal populations, such relationship has not been evaluated in CKD.. Serum concentrations of S-adenosylmethionine (SAM), SAH and total homocysteine (tHcy) were determined by HPLC in 124 CKD stage 5 patients (GFR range 1-11 m/min) and 47 control subjects, and related to renal function, presence of CVD, inflammation and protein-energy wasting (PEW).. The levels of SAM and SAH were higher in CKD patients than in controls. Both SAM (rho=-0.19; P<0.05) and SAH (rho=-0.37, P<0.001) were inversely related to GFR. The concentrations of SAH were significantly higher (P<0.001) in patients with CVD than in non-CVD patients, (683 (201-3057) vs 485 (259-2620) nmol/L; median (range)) as opposed to tHcy levels, which were lower in CVD patients. While SAH was not associated with the presence of inflammation or PEW, it was a significant contributor (OR; 4.9 (CI 1.8-12.8), P<0.001) to CVD in a multinomial logistic regression model (pseudo r(2)=0.31).. Concentrations of serum SAH and SAM in CKD stage 5 patients are associated with renal function, but not with inflammation or PEW. Among the investigated sulfur amino acids, only SAH was independently associated with the presence of clinical signs of CVD. These findings suggest that while tHcy might be influenced by a number of confounding uremic factors, SAH levels may better reflect the putative increased cardiovascular risk of sulfur amino acid alterations in CKD patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Chronic Disease; Female; Homocysteine; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Predictive Value of Tests; S-Adenosylhomocysteine; S-Adenosylmethionine; Sensitivity and Specificity; Severity of Illness Index

S-Adenosylhomocysteine (SAH) is the metabolic precursor of all the homocysteine (Hcy) produced in the body. It is formed by the enzyme SAH hydrolase in a reversible reaction. In a previous study we have shown that plasma SAH is a more sensitive indicator of the risk for cardiovascular disease, and in a second study involving patients with renal disease, we also showed that it is a more sensitive indicator of renal insufficiency than plasma Hcy. However, in the latter study, the patients with renal disease were older and had a variety of other diseases such as diabetes and primary hypertension, which are associated with vascular disease and which could reduce renal function by involvement of the kidneys. Our objective was to rule out these complicating factors as the cause of the elevated SAH in renal disease and determine whether renal insufficiency alone was the cause of the elevated SAH. We therefore measured SAH, Hcy, folate, and vitamin B12 in 23 patients between the ages of 1 and 18 years with a wide range of renal function, but who had none of these complicating factors. Glomerular filtration rate (GFR) was calculated using serum creatinine according to the Schwartz formula. None of the children were deficient in folate or vitamin B12. After adjusting for age, folate, and vitamin B12, there was a modest and insignificant decrease of 0.033 micromol/L of Hcy associated with an increase of 1 mL/min of GFR (95% confidence interval, -0.066 to 0.0002). However, there was a strong and statistically significant association between log(SAH) and log(GFR): P < .0005, R2 = 0.76. This result suggests that plasma SAH rather than Hcy is the metabolite primarily affected in renal disease. We suggest that plasma Hcy elevations that have been linked to vascular disease may be due to elevated SAH resulting from renal insufficiency.

Topics: Adolescent; Child; Child, Preschool; Congenital Hypothyroidism; Folic Acid; Glomerular Filtration Rate; Homocysteine; Humans; Infant; Kidney Diseases; S-Adenosylhomocysteine; Vitamin B 12

Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the AdoMet/S-adenosylhomocysteine (AdoHcy) ratio, also termed as "methylation potential." Since adenosine inhibits in vitro AdoHcy hydrolysis and since adenosine tissue levels increase during hypoxia, it can be predicted that AdoHcy levels may increase in the rat kidney in parallel of those of adenosine. Therefore, the present investigation was performed to assess changes of renal AdoHcy and AdoMet tissue contents during ischemia and after administration of adenosine and homocysteine or both in the ischemic rat kidney. In anesthetized rats ischemia of the kidney was induced by renal artery occlusion for various time intervals. Adenosine and homocysteine were infused into the renal artery of the ischemic kidney. To induce a hyperhomocysteinemia homocysteine was continuously infused. The kidneys were removed and immediately snap-frozen. Tissue contents of AdoHcy, AdoMet, adenosine and adenine nucleotides were analyzed by means of HPLC. Under normoxic condition the tissue contents of AdoHcy, AdoMet and adenosine were 0.7+/-0.05, 44.1+/-1.0 and 3.8+/-0.1nmol/g wet weight, respectively. Renal ischemia for 30min resulted in an increase of AdoHcy levels from 0.7+/-0.05 to 9.1+/-0.6nmol/g wet weight and in a dramatic decrease of the AdoMet/AdoHcy ratio and energy charge from 65.1+/-5.6 to 2.8+/-0.2 and from 0.87+/-0.01 to 0.25+/-0.01, respectively. Application of exogenous adenosine into the ischemic kidney did not result in further AdoHcy accumulation. However, when homocysteine was infused into the ischemic kidney, AdoHcy increased five-fold above control levels, during 5min ischemia. Systemic infusion of homocysteine leads to a reduction of the methylation potential also in the normoxic kidney. We conclude that (i) the methylation potential in the kidney is markedly reduced during ischemia, mainly due to accumulation of AdoHcy; (ii) elevation of AdoHcy tissue content during ischemia is the result of the inhibition of AdoHcy hydrolysis; (iii) homocysteine is rate limiting for AdoHcy synthesis in the ischemic kidney; (iv) under normoxic conditions hyperhomocysteinemia can affect the methylation potential in the renal tissue.

Topics: Adenosine; Animals; Disease Models, Animal; Homocysteine; Hyperhomocysteinemia; Ischemia; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; S-Adenosylhomocysteine; S-Adenosylmethionine