Nitric oxide synthase isoforms play distinct roles during acute peritonitis.
BACKGROUND
Acute peritonitis is the most frequent complication of peritoneal dialysis (PD). Increased nitric oxide (NO) release by NO synthase (NOS) isoforms has been implicated in acute peritonitis, but the role played by the NOS isoforms expressed in the peritoneum is unknown.


METHODS
We investigated the structural and functional consequences of acute peritonitis induced by LPS in wild-type (WT) mice versus knockout mice (KO) for the endothelial NOS (eNOS), the inducible NOS (iNOS) or the neuronal NOS (nNOS).


RESULTS
The level of NO metabolites (NOx) in the dialysate was maximal 18 h after LPS injection. LPS induced a significant increase in the transport of small solutes and decreased ultrafiltration in WT mice. These changes, which occurred without vascular proliferation, were paralleled by the upregulation of nNOS and eNOS, and the induction of iNOS. The transport modifications induced by LPS were significantly reversed in eNOS KO mice, but not modified in mice lacking iNOS or nNOS. In contrast, the increase of dialysate NOx was abolished in iNOS KO mice and significantly reduced in eNOS KO mice, but left unchanged in mice lacking nNOS. Mice lacking iNOS also showed more severe inflammatory changes, and a trend towards increased mortality following LPS.


CONCLUSIONS
These data demonstrate specific roles for NOS isoforms in the peritoneal membrane and suggest that selective eNOS inhibition may improve peritoneal transport during acute peritonitis.
Ni
Jie
J
Université catholique de Louvain Medical School, Brussels, Belgium.
McLoughlin
Rachel M
RM
Brodovitch
Alexandre
A
Moulin
Pierre
P
Brouckaert
Peter
P
Casadei
Barbara
B
Feron
Olivier
O
Topley
Nicholas
N
Balligand
Jean-Luc
JL
Devuyst
Olivier
O
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000502:physiology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000502:physiology*; D010537:Peritoneum / Q000201:enzymology / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*
D007527:Isoenzymes; D008070:Lipopolysaccharides; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
J Biol Chem. 2003 Jul 18;278(29):26480-7
12740377
Cell. 1993 Dec 31;75(7):1273-86
7505721
J Am Soc Nephrol. 2001 Oct;12(10):2146-2157
11562414
Eur J Clin Invest. 1987 Feb;17(1):43-52
3106050
Kidney Int Suppl. 1996 Nov;56:S17-21
8914049
FASEB J. 1998 Jul;12(10):773-90
9657518
Kidney Int. 2000 Jan;57(1):332-8
10620216
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651-5
1675786
J Am Soc Nephrol. 2003 Dec;14(12):3205-16
14638919
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10089-93
7524082
Curr Opin Immunol. 1991 Feb;3(1):65-70
1711326
FASEB J. 1997 Oct;11(12):955-64
9337148
J Clin Invest. 1997 Nov 1;100(9):2146-52
9410890
J Am Soc Nephrol. 1999 Oct;10(10):2185-96
10505696
Kidney Int. 2005 May;67(5):2021-31
15840053
J Clin Invest. 1994 Dec;94(6):2231-6
7527428
Am J Physiol. 1999 Jun;276(6):H1943-50
10362674
FEBS Lett. 1993 Jan 25;316(2):175-80
7678401
Am J Respir Crit Care Med. 2001 Mar;163(4):977-82
11282776
Am J Kidney Dis. 1999 Feb;33(2):383-8
10023655
Neuroscience. 2004;128(2):421-30
15350652
Curr Top Med Chem. 2007;7(1):97-114
17266598
Nephrol Dial Transplant. 2001 Mar;16(3):675-8
11239067
J Mol Cell Cardiol. 2004 Nov;37(5):939-45
15522271
Kidney Int. 2002 Feb;61(2):375-86
11849377
J Auton Nerv Syst. 1994 Sep;49(1):1-14
7525687
Gastroenterology. 1997 Mar;112(3):1022-7
9041266
Cardiovasc Pathol. 2003 Mar-Apr;12(2):82-90
12684163
Eur J Immunol. 1996 Mar;26(3):511-6
8605914
N Engl J Med. 1998 Feb 12;338(7):436-45
9459648
J Histochem Cytochem. 2003 Feb;51(2):151-8
12533523
Thromb Haemost. 1997 Jan;77(1):163-7
9031468
Curr Drug Targets Inflamm Allergy. 2002 Mar;1(1):89-108
14561209
Arterioscler Thromb Vasc Biol. 1999 Nov;19(11):2584-90
10558999
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13176-81
8917564
Circ Res. 2008 Sep 12;103(6):591-7
18688046
Am J Physiol. 1993 Sep;265(3 Pt 2):H862-7
8214120
Gen Pharmacol. 1997 Aug;29(2):159-66
9251894
J Am Soc Nephrol. 2000 Apr;11(4):717-728
10752531
Trends Pharmacol Sci. 2003 Feb;24(2):91-5
12559774
Perit Dial Int. 2005 Feb;25 Suppl 3:S11-4
16048247
Nature. 1995 Jun 1;375(6530):408-11
7539113
Pharmacol Rev. 1991 Jun;43(2):109-42
1852778
Kidney Int. 2001 Dec;60(6):2343-50
11737609
Adv Pharmacol. 1995;34:113-53
8562430
J Am Soc Nephrol. 2002 Jan;13 Suppl 1:S104-16
11792770
Am J Physiol. 1992 Feb;262(2 Pt 2):H611-5
1539722
Am J Physiol Regul Integr Comp Physiol. 2003 Mar;284(3):R628-38
12571071
J Lab Clin Med. 1998 Oct;132(4):329-40
9794705