Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure. Effects of salt intake.

Welch, William J.; Wilcox, Christopher S.

doi:10.1172/jci119761

Cited by 48 publications

(46 citation statements)

References 25 publications

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“…Intracellular protein hydrolysis releases free ADMA. In exchange for L-arginine and other cationic amino acids, ADMA is transported out of cells through cationic amino acid transporters (CAT) (Baylis, 2006;Closs et al, 1997;Welch and Wilcox, 1997) where it can have effects at sites distal from its production. Although we are not aware of any studies demonstrating an effect of CS on PRMT expression or function, Zhang et al (2006) reported a significant reduction in the expression of CAT1 in human endothelial cells following a brief exposure to 10% CSE.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

Staab

Weigel

Xiao

et al. 2014

Journal of Immunotoxicology

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There is increasing evidence that the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethyl-arginine (ADMA) is involved in the pathogenesis of chronic lung diseases. One important regulator of this molecule is the ADMA-metabolizing enzyme dimethyl-arginine dimethyl-aminohydrolase (DDAH). The objective of this study was to determine whether perturbation of the ADMA-DDAH pathway contributes to lung inflammation following exposure to cigarette smoke (CS). For these studies, wild-type and DDAH transgenic mice were sham or CS-exposed. Serum ADMA levels were determined by mass spectrometry. ADMA content and DDAH expression were also visualized in mouse lung tissue by immunohistochemistry. DDAH expression was determined by real-time quantitative PCR (qPCR). Inflammation was assessed by H&E staining and analyses of total cell counts and fluid tumor necrosis factor (TNF)-levels (using ELISA) in lung lavage fluid. NF-B binding activity in mouse lung epithelial (LA-4) cells was assessed by a transcription factor-binding assay. The results indicated that the concentration of serum ADMA was increased following exposure to CS, and this corresponded with increased ADMA content in bronchial epithelial cells in lung tissue. Total lung DDAH expression was significantly decreased in lung tissue and cultured LA-4 cells following CS exposure. Addition of exogenous ADMA increased CSE-mediated NF-B binding activity and TNFa production in LA-4 cells more than 2-fold compared to that in CSE-exposed controls. CS-mediated lung inflammation was significantly attenuated in DDAH transgenic mice compared to in wild-type controls. These findings demonstrated that lung ADMA metabolism was altered in mice following CS exposure and suggested that ADMA played a role in CS-mediated inflammation through increasing the presence of inflammatory mediators in lung epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

Staab

Weigel

Xiao

et al. 2014

Journal of Immunotoxicology

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“…However, an increase in DDAH-2 in the juxtaglomerular apparatus could reduce local levels of ADMA, including within the macula densa cells. nNOS is expressed heavily in macula densa cells where it blunts vasoconstriction of the adjacent renal afferent arteriole, for example by the TGF process, thereby increasing the nephron GFR (212,220). NO generated by macula densa nNOS is implicated in the regulation of renal hemodynamics, for example the renal vasodilation accompanying high salt intake (219).…”

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

“…NO generated by macula densa nNOS is implicated in the regulation of renal hemodynamics, for example the renal vasodilation accompanying high salt intake (219). Microperfusion of ADMA into the macula densa segment of the rat nephron enhances TGF and reduces glomerular capillary pressure by a mechanism that apparently entails inhibition of NOS since it can be prevented by microperfusion of L-arginine (212). Thus upregulation of DDAH-2 in the macula densa cells of the Fig.…”

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

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Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

287

301

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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

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“…SDMA does not inhibit NOS but, like the other methylarginine analogues, can compete with arginine for cellular uptake via system y ϩ (3,4). ADMA increases the tone of rat aortic rings (5), raises blood pressure in guinea pigs (6), and reduces resting forearm blood flow in humans (6).…”

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confidence: 99%

Expression of NG,NG-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney

et al. 2008

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OBJECTIVE-The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) is generated by protein arginine N-methyltransferase (PRMT)-1 and is metabolized by N G ,N Gdimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that increased serum ADMA (S ADMA ) in the streptozotocin (STZ)-induced diabetic rat model of diabetes is mediated by an angiotensin receptor blocker-sensitive change in DDAH or PRMT expression. RESEARCH DESIGN AND METHODS-Datawere compared from four groups of rats: sham-injected controls, untreated STZ-induced diabetic rats at 4 weeks, STZ-induced diabetic rats administered the angiotensin II (Ang II) receptor blocker telmisartan for 2 weeks, and control rats administered telmisartan for 2 weeks.RESULTS-Immunostaining and Western blotting of microdissected nephron segments localized DDAH I in the proximal tubules and DDAH II in the glomeruli, afferent arterioles, macula densa, and distal nephron. Renal Ang II and S ADMA increased with diabetes but were normalized by 2 weeks of telmisartan. DDAH I expression was decreased in diabetic kidneys, while DDAH II expression was increased. These changes were reversed by telmisartan, which also reduced expression of PRMT-1 and -5. Telmisartan increased expressions of DDAH I but decreased DDAH II in Ang II-stimulated kidney slices ex vivo. CONCLUSIONS-RenalAng II and S ADMA are increased in insulinopenic diabetes. They are normalized by an Ang II receptor blocker, which increases the renal expression of DDAH I, decreases PRMT-1, and increases renal NO metabolites.

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Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure. Effects of salt intake.

Abstract: These studies tested the hypothesis that delivery and/or cellular uptake of L -arginine limits macula densa nitric oxide generation and actions on tubuloglomerular feedback (

Cited by 48 publications

References 25 publications

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Expression of NG,NG-Dimethylarginine Dimethylaminohydrolase and Protein Arginine N-Methyltransferase Isoforms in Diabetic Rat Kidney

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