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ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide
Chronic kidney disease (CKD) is associated with decreased renal nitric oxide (NO) production and increased plasma levels of methylarginines. The naturally occurring guanidino-methylated arginines N-monomethyl-l-arginine (l-NMMA) and asymmetric dimethyl-l-arginine (ADMA) inhibit NO synthase activity....
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Published in: | American Journal of Physiology - Renal Physiology 2009-06, Vol.296 (6), p.F1386-F1395 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Chronic kidney disease (CKD) is associated with decreased renal nitric oxide (NO) production and increased plasma levels of methylarginines. The naturally occurring guanidino-methylated arginines N-monomethyl-l-arginine (l-NMMA) and asymmetric dimethyl-l-arginine (ADMA) inhibit NO synthase activity. We hypothesized that ADMA and l-NMMA compromise the integrity of the glomerular filtration barrier via NO depletion. We studied the effect of ADMA on albumin permeability (P(alb)) in isolated glomeruli and examined whether this effect involves NO- and superoxide (O(2)(*-))-dependent mechanisms. ADMA at concentrations found in circulation of patients with CKD decreased cGMP and increased P(alb) in a dose-dependent manner. A similar increase in P(alb) was caused by l-NMMA but at a concentration two orders of magnitude higher than that of ADMA. NO donor DETA-NONOate or cGMP analog abrogated the effect of ADMA on P(alb). The SOD mimetic tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in P(alb). The NO-independent soluble guanylyl cyclase (sGC) activator BAY 41-2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in P(alb). Furthermore, sGC incapacitation by the heme site-selective inhibitor ODQ increased P(alb). We conclude that ADMA compromises the integrity of the filtration barrier by altering the bioavailability of NO and O(2)(*-) and that NO-independent activation of sGC preserves the integrity of this barrier under conditions of NO depletion. NO-independent activation of sGS may be a useful pharmacotherapeutic approach for preservation of glomerular function in CKD thereby reducing the risk for cardiovascular events. |
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ISSN: | 1931-857X 0363-6127 1522-1466 |
DOI: | 10.1152/ajprenal.90369.2008 |