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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/F1386    most recent 90369.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sharma, M. Articles by Lianos, E. A. PubMed PubMed Citation Articles by Sharma, M. Articles by Lianos, E. A.

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

¹Division of Nephrology, Department of Medicine and Kidney Disease Center, and ³Cardiovascular Center and Cardiovascular Medicine/Department of Medicine, Medical College of Wisconsin; Milwaukee, Wisconsin; ²George Livanos Laboratory, Department of Critical Care and Pulmonary Medicine, University of Athens School of Medicine, Athens, Greece; and ⁴Kidney Institute, University of Kansas Medical Center, and ⁵Renal Section, Veterans Administration Medical Center, Kansas City, Missouri

Submitted 16 June 2008 ; accepted in final form 16 March 2009

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 (O₂^–)-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 O₂^– 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