Submitted on June 16, 2008
Revised on February 25, 2009
Accepted on March 16, 2009
ADMA Injures Glomerular Filtration Barrier: Role of Nitric Oxide and Superoxide
Mukut Sharma1*, Zongmin Zou2, Hiroto Miura1, Andreas Papapetropoulos2, Ellen T. McCarthy3, Ram Sharma4, Virginia J. Savin1, and Elias A Lianos5
1 Medical College of Wisconsin
2 University of Athens School of Medicine, Athens, Greece
3 Kansas University Medical Center, Kansas City, KS
4 V.A. Medical Center
5 UMDNJ-Robert Wood Johnson Medical School
* To whom correspondence should be addressed. E-mail: msharma{at}mcw.edu.
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 (NOS) 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 (Palb) 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 Palb in a dose-dependent manner. A similar increase in Palb 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 Palb. The SOD mimetic Tempol or the NAD(P)H oxidase inhibitor apocynin also prevented the ADMA-induced increase in Palb. The NO-independent soluble guanylyl cyclase (sGC) activator BAY41-2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in Palb. Further, sGC incapacitation by the heme site selective inhibitor ODQ increased Palb. 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.
