Nitric oxide inhibits glomerular TGF-beta signaling via SMOC-1.
Cytokines and nitric oxide (NO) stimulate rat mesangial cells to synthesize and secrete inflammatory mediators. To understand better the signaling pathways that contribute to this response, we exposed rat mesangial cells to the prototypic inflammatory cytokine IL-1beta and analyzed the changes in the pattern of gene expression. IL-1beta downregulated the gene encoding the matricellular glycoprotein secreted modular calcium-binding protein 1 (SMOC-1) in mesangial cells. Inflammatory cytokines attenuated SMOC-1 mRNA and protein expression through endogenous production of NO, which activated the soluble guanylyl cyclase. Silencing SMOC-1 expression with small interfering RNA decreased the formation of TGF-beta, reduced SMAD binding to DNA, and decreased mRNA expression of genes regulated by TGF-beta. In a rat model of anti-Thy-1 glomerulonephritis, glomerular SMOC-1 mRNA and protein decreased and inducible NO synthase expression increased simultaneously. Treatment of nephritic rats with the inducible NO synthase-specific inhibitor l-N(6)-(1-iminoethyl)-lysine prevented SMOC-1 downregulation. In summary, these data suggest that NO attenuates SMOC-1 expression in acute glomerular inflammation, thereby limiting TGF-beta-mediated profibrotic signaling.
Dreieicher
Ellen
E
Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Beck
Karl-Friedrich
KF
Lazaroski
Sandra
S
Boosen
Meike
M
Tsalastra-Greul
Wasiliki
W
Beck
Martina
M
Fleming
Ingrid
I
Schaefer
Liliana
L
Pfeilschifter
Josef
J
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D007518:Isoantibodies / Q000276:immunology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D053583:Interleukin-1beta; D007518:Isoantibodies; D015676:Osteonectin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; C543959:Smoc1 protein, rat; D053773:Transforming Growth Factor beta1; C035678:anti-Thy antibody; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase