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. 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.
Sharma
Mukut
M
Division of Nephrology, Dept. of Medicine, Kidney Disease Center, Medical College of Wisconsin, M-4160, Nephrology/CVC/MEB, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. msharma@mcw.edu
Zhou
Zongmin
Z
Miura
Hiroto
H
Papapetropoulos
Andreas
A
McCarthy
Ellen T
ET
Sharma
Ram
R
Savin
Virginia J
VJ
Lianos
Elias A
EA
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000633:toxicity*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D016166:Free Radical Scavengers / Q000494:pharmacology; D050533:Glomerular Basement Membrane / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D011407:Propane / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000633:toxicity
D000418:Albumins; D000873:Anthracenes; D016166:Free Radical Scavengers; D018160:Receptors, Cytoplasmic and Nuclear; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D011407:Propane