Interactions between inducible nitric oxide synthase and heme oxygenase-1 in glomerulonephritis.
BACKGROUND
In anti-glomerular basement membrane (GBM) nephritis, inducible nitric oxide synthase (iNOS) and heme oxygenase (HO-1) are co-induced. Moreover, in glomerular mesangial cells iNOS-derived nitric oxide (NO) production stimulates HO-1 while HO-1 activation reduces iNOS expression/activity. These observations prompted us to explore regulatory interactions between iNOS and HO-1 in anti-GBM nephritis.


METHODS
Rats with anti-GBM nephritis were pretreated with the iNOS inhibitor l-N6-(1-iminoethyl) lysine (L-NIL) or with the HO-1 inducer hemin. Glomerular HO-1 levels were assessed by Western blot analysis. iNOS activity was assessed by calculating conversion of l-arginine to l-citrulline.


RESULTS
iNOS inhibition reduced glomerular HO-1 levels without altering the inflammatory response to anti-GBM antibody induced injury. Induction of HO-1 reduced glomerular iNOS activity.


CONCLUSIONS
In anti-GBM nephritis iNOS up-regulates HO-1 presumably via high output NO production. Suprainduction of HO-1 attenuates iNOS activity. This negative feedback interaction points to HO-1 as a target for pharmacologic manipulation to reduce activity of prooxidant heme containing enzymes such as iNOS.
Datta
Prasun K
PK
Division of Nephrology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, P.O. Box 19, MEB 412,New Brunswick, NJ, USA.
Gross
Eugene J
EJ
Lianos
Elias A
EA
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000201:enzymology*; D004790:Enzyme Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D051547:Heme Oxygenase-1; D007678:Kidney Glomerulus / Q000201:enzymology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D015854:Up-Regulation
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D008239:Lysine