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

Mukut Sharma, Zongmin Zhou, Hiroto Miura, Andreas Papapetropoulos, Ellen T. McCarthy, Ram Sharma, Virginia J. Savin, Elias A. Lianos

Research output: Contribution to journalArticle

37 Scopus citations

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 (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 BAY 41-2272, at concentrations that increased glomerular cGMP production, attenuated the ADMA-induced increase in Palb. Furthermore, 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 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.

Original languageEnglish (US)
Pages (from-to)F1386-F1395
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 2009

Keywords

  • Cardiorenal disease
  • Chronic kidney disease

ASJC Scopus subject areas

  • Physiology
  • Urology

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