ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide

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Publisher: American Physiological Society
Document Type: Author abstract; Report
Length: 247 words

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Abstract :

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.sub.alb]) in isolated glomeruli and examined whether this effect involves NO- and superoxide ([O.sup.*-.sub.2])-dependent mechanisms. ADMA at concentrations found in circulation of patients with CKD decreased cGMP and increased [P.sub.alb] in a dose-dependent manner. A similar increase in [P.sub.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.sub.alb] . The SOD mimetic tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in [P.sub.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.sub.alb] . Furthermore, sGC incapacitation by the heine site-selective inhibitor ODQ increased [P.sub.alb]. We conclude that ADMA compromises the integrity of the filtration barrier by altering the bioavailability of NO and [O.sup.*-.sub.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. chronic kidney disease; cardiorenal disease

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Gale Document Number: GALE|A202437626