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

36 Citations (Scopus)

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 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Fingerprint

Glomerular Filtration Barrier
Superoxides
Nitric Oxide
omega-N-Methylarginine
Chronic Renal Insufficiency
Arginine
N,N-dimethylarginine
Nitric Oxide Donors
NADPH Oxidase
Heme
Nitric Oxide Synthase
Biological Availability
Albumins
Permeability

Keywords

  • Cardiorenal disease
  • Chronic kidney disease

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

ADMA injures the glomerular filtration barrier : Role of nitric oxide and superoxide. / Sharma, Mukut; Zhou, Zongmin; Miura, Hiroto; Papapetropoulos, Andreas; McCarthy, Ellen T.; Sharma, Ram; Savin, Virginia J.; Lianos, Elias A.

In: American Journal of Physiology - Renal Physiology, Vol. 296, No. 6, 01.06.2009.

Research output: Contribution to journalArticle

Sharma, Mukut ; Zhou, Zongmin ; Miura, Hiroto ; Papapetropoulos, Andreas ; McCarthy, Ellen T. ; Sharma, Ram ; Savin, Virginia J. ; Lianos, Elias A. / ADMA injures the glomerular filtration barrier : Role of nitric oxide and superoxide. In: American Journal of Physiology - Renal Physiology. 2009 ; Vol. 296, No. 6.
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AU - McCarthy, Ellen T.

AU - Sharma, Ram

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