Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.
Arginase shares a common substrate, L-arginine, with nitric oxide synthase (NOS). Both enzymes are active at inflammatory sites. To understand regulation of arginase and its relationship to nitric oxide (NO) production, we studied effects of NG-hydroxy-L-arginine (HOArg) and interleukin-4 (IL-4) on urea and NO2- synthesis by glomeruli during rat immune glomerulonephritis and compared these with macrophages and glomerular mesangial cells (MC). In nephritic glomeruli, elicited macrophages, and MC stimulated with IL-1 and adenosine 3',5'-cyclic monophosphate agonists, increased arginase and induced NOS activity was found. Urea production was inhibited by HOArg and increased by IL-4. NO inhibition [NG-monomethyl-L-arginine (L-NMMA)] increased arginase activity in nephritic glomeruli and macrophages but not MC. NO2- synthesis was inhibited by L-NMMA and IL-4. It was increased with HOArg under conditions of NO inhibition. In contrast, in normal glomeruli and basal MC, where there was no induced NO synthesis, IL-4 had no effect on arginase activity, whereas HOArg consistently reduced it in glomeruli only. Type II arginase (Arg II) mRNA was detected in normal glomeruli; nephritic glomeruli expressed both Arg I and Arg II mRNAs. This is the first demonstration of arginase modulation in glomeruli and MC and of the expression of arginase isoforms in glomeruli. The differential responses to two endogenous compounds generated by inflammation suggest this may be part of coordinated regulation of arginase and inducible NOS in immune injury, whereby arginase is inhibited during high-output NO production and stimulated with NO suppression. This, together with control of arginase and NOS isoforms, may be important in controlling the balance of inflammatory and repair mechanisms.
Waddington
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SN
Department of Histopathology, Imperial College School of Medicine at St. Mary's, London, United Kingdom.
Tam
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FW
Cook
H T
HT
Cattell
V
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D005920:Glomerular Mesangium / Q000201:enzymology*; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000201:enzymology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D009393:Nephritis / Q000201:enzymology*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D007375:Interleukin-1; D007527:Isoenzymes; D009573:Nitrites; D015847:Interleukin-4; C068309:N(omega)-hydroxyarginine; D002772:Cholera Toxin; D001120:Arginine; D000242:Cyclic AMP; D001119:Arginase; D015056:1-Methyl-3-isobutylxanthine